SUV Family Histone Methyltransferases Modulate Nuclear Lamin A and Drive Tumorigenesis: Integrative Pan-Cancer TCGA analysis and Experimental Evidence

SUV Family Histone Methyltransferases Modulate Nuclear Lamin A and Drive Tumorigenesis: Integrative Pan-Cancer TCGA analysis and Experimental Evidence | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article SUV Family Histone Methyltransferases Modulate Nuclear Lamin A and Drive Tumorigenesis: Integrative Pan-Cancer TCGA analysis and Experimental Evidence Subhadip Kundu, Abdur Rahmaan Akhtar, Arun Kumar, Ashok Sharma This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8137620/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Apr, 2026 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Epigenetic regulation of chromatin structure is a key determinant of transcriptional control and nuclear organization in cancer. Among histone lysine methyltransferases, SUV39H1 and SUV39H2 catalyze the trimethylation of histone H3 lysine 9 (H3K9me3), establishing repressive heterochromatin domains that are essential for genomic stability. However, their pan-cancer expression dynamics, prognostic value, and structural implications remain poorly defined. In this study, we performed an integrative analysis of SUV39H1 and SUV39H2 across the Cancer Genome Atlas (TCGA) cohort to investigate their expression, prognostic relevance, associations with the immune landscape, and interactions with nuclear lamina genes. Both enzymes were significantly overexpressed in multiple tumor types, with SUV39H2 showing particularly high expression in high-grade serous ovarian cancer (HGSOC), where elevated levels correlated with poor overall survival (HR = 3.27, p < 0.001). Immune infiltration analysis revealed that high SUV39H2 expression was inversely associated with tumor-infiltrating lymphocytes, indicating an immunosuppressive tumor microenvironment. Correlation studies demonstrated strong positive associations between SUV39H1/H2 and Lamin B genes (LMNB1, LMNB2), implicating their role in maintaining nuclear architecture and heterochromatin tethering. Conversely, Lamin A (LMNA) exhibited weak or negative correlation with SUV39 enzymes. Functional validation in A2780 ovarian cancer cells demonstrated that pharmacological inhibition of SUV39H2 by Chaetocin resulted in the upregulation of Lamin A, indicating epigenetic repression of LMNA by SUV39H2. Collectively, our findings uncover a novel link between SUV39H2, chromatin–lamina interactions, and immune evasion in ovarian cancer, providing a rationale for targeting SUV39H2 in therapeutic epigenetic interventions. Biological sciences/Cancer Biological sciences/Computational biology and bioinformatics Biological sciences/Genetics Health sciences/Oncology SUV39H2 H3K9me3 ovarian cancer Lamin B epigenetic repression immune evasion Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. Introduction Epigenetic modifications play a central role in regulating chromatin structure, transcriptional dynamics, and genome stability (Bannister and Kouzarides 2011 ; Allis and Jenuwein 2016 ). Among the diverse set of chromatin-modifying enzymes, histone lysine methyltransferases (KMTs) establish and maintain transcriptionally permissive or repressive chromatin states by depositing specific methyl groups on histone tails (Black et al, 2012 ; Husmann & Gozani,2019). One of the most critical histone modifications associated with transcriptional repression is the trimethylation of histone H3 at lysine 9 (H3K9me3). This repressive mark is enriched in constitutive heterochromatin regions, repetitive DNA elements, and lamina-associated domains (LADs), thereby contributing to nuclear compartmentalization, gene silencing, and chromosomal integrity (Saksouk et al., 2015 ; Becker et al.,2016). The establishment of this mark is largely mediated by the Suppressor of Variegation (SUV) family of histone methyltransferases, which includes SUV39H1, SUV39H2, and closely related enzymes (Peters et al. 2001 ). The SUV family is evolutionarily conserved and has been studied extensively for its role in heterochromatin formation. SUV39H1 was initially identified in Drosophila as a key regulator of position-effect variegation (Elgin and Reuter 2013 ) and later shown in mammals to be the principal enzyme responsible for catalyzing H3K9me3 at pericentric heterochromatin (Padeken et al. 2022 ). SUV39H2, although less well-characterized, exhibits similar catalytic activity and cooperates with SUV39H1 in establishing heterochromatin domains, particularly during development and germline specification (Weirich et al.,2021). Both enzymes act as epigenetic scaffolds, recruiting heterochromatin protein 1 (HP1) and interacting with nuclear lamina components, thereby linking chromatin compaction to nuclear architecture (Maison and Almouzni 2004 ). Collectively, the SUV family ensures the maintenance of silent chromatin, suppresses transposable elements, and stabilizes the three-dimensional nuclear landscape. Increasing evidence suggests that the deregulation of SUV family enzymes contributes to cancer biology (Li et al., 2019 ; Saha and Muntean,2021). Aberrant SUV39H1 expression has been reported in a wide range of tumors, including kidney (Wang et al. 2020 ), liver (Zhang et al. 2023a ), breast (Huang et al. 2023 ), brain (Li et al. 2024 ), and haematological cancers (Devin et al. 2015 ; Zhang et al. 2023b ), where it promotes tumor cell survival through silencing of tumor suppressor genes, facilitating DNA repair evasion, and fostering an immunosuppressive microenvironment. In parallel, SUV39H2 has been shown to stabilize oncogenic transcriptional programs, inhibit apoptosis, and maintain stem-like properties in cancer cells (Li et al. 2019 ). Importantly, alterations in SUV enzyme activity are often coupled with global changes in heterochromatin distribution and nuclear morphology — features frequently observed in aggressive cancers. Recent studies have further highlighted their involvement in chemoresistance (Wang et al.,2019), underscoring the clinical relevance of targeting SUV family members in oncology. Despite these insights, our understanding of the pan-cancer role of SUV family histone methyltransferases remains limited. Most studies to date have focused on individual tumor types, yielding fragmented insights into their oncogenic potential. Moreover, while SUV enzymes are strongly linked to heterochromatin formation and nuclear architecture, their relationship with nuclear lamina proteins, such as lamin A, and their contribution to large-scale nuclear reorganization in cancer, remain poorly defined. A comprehensive assessment of their expression patterns, prognostic significance, and molecular associations across diverse cancer types has not been undertaken. To address this gap, we conducted an integrated pan-cancer analysis of the Cancer Genome Atlas (TCGA) dataset to evaluate the SUV family of histone methyltransferases systematically. By analyzing their expression across multiple tumor types, investigating their prognostic impact, and exploring their association with nuclear architecture–related pathways, we provide the first large-scale evidence of how SUV enzymes contribute to tumorigenesis in a pan-cancer context. Our findings not only highlight their importance as epigenetic drivers of cancer but also open new avenues for exploring SUV family members as potential biomarkers and therapeutic targets in precision oncology. 2. Materials and Methods 2.1. Mammalian cell culture and drug treatment: In this study, High-grade serous ovarian cancer (HGSOC) cell lines, namely A2780, IGROV1, OVCAR3, OVCAR4, OVCAR5, and OVCAR8, were used. All cell lines were obtained from the American Type Culture Collection (ATCC), which was generously gifted by Prof. Adam R. Karpf, University of Nebraska Medical Center, Omaha, USA, and maintained according to the following protocol. Cells were cultured in RPMI 1640 medium supplemented with 10% FBS and 1% antibiotic and antimycotic solution and incubated in a humidified chamber at 37ºC in the presence of 5% CO 2 . For drug treatment, chaetocin, a Suv39h2/h2 blocker, was used. Cells were seeded at a density of 3×10 5 cells in a 60mm cell culture plate. Chaetocin treatment was administered to the A2780 cell line at final concentrations of 300 nM and 600 nM from a 1mg/ml stock solution and incubated for 24 hours in a humidified chamber at 37°C in the presence of 5% CO 2 . Protein samples were collected after 24 hours of treatment. 2.2. Western blotting: Western blotting was performed to evaluate the expression of SUV39H1 and SUV39H2 across ovarian cancer cell lines (A2780, IGROV1, OVCAR3, OVCAR4, OVCAR5, OVCAR8) and to assess Lamin A protein levels following Chaetocin treatment in A2780 cells. Cells were cultured in 60 mm tissue culture dishes using RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% antibiotic-antimycotic solution, maintained at 37°C in a humidified 5% CO₂ incubator. When cultures reached approximately 70–80% confluence or after 24 hours of Chaetocin treatment (300 nM and 600 nM), cells were harvested by scraping in ice-cold PBS and lysed using RIPA buffer (50 mM Tris-HCl, pH 7.4; 150 mM NaCl; 1% NP-40; 0.5% sodium deoxycholate; 0.1% SDS) supplemented with protease and phosphatase inhibitor cocktails. Lysates were incubated on ice for 30 minutes with intermittent vortexing, followed by centrifugation at 14,000 rpm for 15 minutes at 4°C to remove cellular debris. The supernatants were collected, and protein concentrations were determined using the Bradford assay (Bio-Rad). Equal amounts of total protein (30 µg) were mixed with 4× Laemmli sample buffer, boiled at 95°C for 5 minutes, and separated by SDS-PAGE on 10–12% polyacrylamide gels. Proteins were electro-transferred onto PVDF membranes (Millipore). Membranes were blocked with 5% BSA in TBST (20 mM Tris-HCl, 150 mM NaCl, 0.1% Tween-20) for 1 hour at room temperature and incubated overnight at 4°C with primary antibodies against SUV39H1 (Abcam, ab12405, 1:1000), SUV39H2 (Abcam, ab184500, 1:1000), and Lamin A/C (Cell Signaling Technology, #4777, 1:2000). After washing, membranes were incubated with HRP-conjugated secondary antibodies (1:5000) for 1 hour at room temperature. Protein bands were visualized using enhanced chemiluminescence (ECL) detection reagent (Biorad) and imaged with a ChemiDoc imaging system (GE). β-actin (Cell Signaling Technology, #4970, 1:5000) served as the loading control. Densitometric quantification of protein bands was performed using ImageJ software, and relative expression levels were normalized to β-actin. 2.3. Immunofluorescence and confocal microscopy imaging: A2780 ovarian cancer cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C in a humidified atmosphere containing 5% CO₂. Cells were seeded into 8-well chambered slide and treated with chaetocin (600 nM) for 24 hours. Following treatment, cells were fixed with 4% paraformaldehyde for 10 minutes at room temperature and then permeabilized with 0.1% Triton X-100 in PBS for an additional 10 minutes. After blocking with 5% normal goat serum for 1 hour, cells were incubated overnight at 4°C with anti-Lamin A antibody (Abcam, 1:200 dilution). The next day, cells were washed and incubated with Alexa Fluor 488-conjugated secondary antibody (Invitrogen, 1:600) for 1 hour at room temperature, followed by nuclear counterstaining with DAPI (0.5 µg/mL). Coverslips were mounted with Vectashield Antifade Mounting Medium (Vector Laboratories) and imaged using a Zeiss LSM 980 confocal microscope, with identical acquisition settings applied to all samples. Mid-optical sections of the confocal Z-stack images are shown in the figures. 2.4. In silico gene expression analysis of SUV39H1 and SUV39H2 from TCGA datasets: The mRNA expression analysis for the SUV39H1 and SUV39H2 genes in the pan-cancer model was analysed using TCGA RNA-sequencing datasets through the TIMER2.0 [ https://compbio.cn/timer2/ ] webtool (Li et al. 2020 ). Pan-cancer dot matrix for SUV39H1 and SUV39H2 were calculated using TCGA data through TNMplot web tool [ https://tnmplot.com](Bartha and Győrffy 2021 ). The mRNA expression of SUV39H1 and SUV39H2 was further analyzed in ovarian cancer samples using microarray gene expression datasets from the Gene Expression Omnibus (GEO) database ( https://www.ncbi.nlm.nih.gov/geo/ ), with the accession number GSE27651. Briefly, datasets were analyzed using the GEO2R web tool, and samples were classified into Normal (N = 6) and High-grade serous ovarian carcinoma (N = 19) based on metadata from the submission associated with GSE27651. Gene expression (Transcripts per Million) for SUV39H1 and SUV39H2 was extracted and plotted using GraphPad PRISM software, and P-values were calculated using the Mann-Whitney t-test. 2.5. Survival analysis: In this study, survival analysis was employed to investigate the relationship between SUV39H1 and SUV39H2 expression and patient outcomes. Overall survival (OS) was defined as the time from initial cancer diagnosis to the date of death from any cause. Disease-free survival (DFS) was defined as the duration following treatment completion during which patients exhibited no clinical or radiological evidence of disease recurrence. The GEPIA2 web tool ( http://gepia2.cancer-pku.cn/ ) was utilized to conduct these analyses (Tang et al. 2019 ; Li et al. 2021 ). Patient cohorts were stratified based on SUV39H1 or SUV39H2 mRNA expression levels, specifically comparing a group exhibiting high expression of SUV39H1 or SUV39H2 to a group with low expression of these genes. The statistical significance was calculated using the log-rank test. 2.6. Tumor Infiltrating Lymphocyte (TIL) Analysis using TCGA RNA-seq data: To understand the relationship between SUV39H2 gene expression/promoter methylation and the presence of tumor-infiltrating lymphocytes (TILs), the TISIDB webtool [ http://cis.hku.hk/TISIDB/index.php (Ru et al. 2019 )] was utilized. Pan-cancer correlations were calculated for each TILs and SUV39H2 gene expression and methylation and presented in the form of a heatmap. Scatterplots of SUV39H2 expression/methylation, as well as the correlation between individual TIL, were shown for statistically significant results. P < 0.05 was considered as statistically significant. 2.7. Gene correlation analysis: To explore the correlation between lamin genes (LMNB1, LMNB2, and LMNA) and SUV39H1/H2 in pan-cancer and ovarian cancer, the GEPIA2 webtool [ http://gepia2.cancer-pku.cn (Tang et al. 2019 ; Li et al. 2021 )] was utilized. GEPIA2 is a valuable resource that leverages data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project. Spearman Correlation between gene expression was computed and scatter plots were generated to visualize expression relationships. Statistical significance was set at p < 0.05. Pan-Cancer correlations were performed using aggregated TCGA RNA-seq data comprising 33 cancer types. Pan-cancer heatmap of Spearman correlation between SUV39H1 and SUV39H2 and lamin genes were calculated using TIMER2.0 webtool [ https://compbio.cn/timer2/ ] (Li et al. 2020 ). 2.8. Statistical Analysis for experimental data: The drug treatment experiments were repeated 3 times, and densitometric quantification of western blot images was performed using ImageJ software. Statistical analysis of variance (ANOVA) was performed, and P < 0.05 (N = 3 replicates) was considered statistically significant. For Immunofluorescence imaging, images were processed with ImageJ software, and fluorescence intensities were calculated and plotted using GraphPad PRISM software. Statistical analysis was performed using the Mann-Whitney t- test, and P < 0.05 was considered statistically significant. 3. Results 3.1. Pan-cancer expression profile of SUV39H1 and SUV39H2 To elucidate the transcriptional landscape of the SUV39 family of histone methyltransferases, we systematically analyzed the expression of SUV39H1 and SUV39H2 across 33 tumor types from The Cancer Genome Atlas (TCGA) dataset. Expression levels (log₂ TPM) were compared between tumor and normal samples, and distinct overexpression patterns were observed for both members across multiple types of cancer. SUV39H1 displayed a widespread and significant upregulation across numerous malignancies, including breast invasive carcinoma (BRCA), cholangiocarcinoma (CHOL), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC) (Fig. 1 a). The degree of overexpression was particularly striking in KIRC, GBM, and CHOL, where SUV39H1 levels were several-fold higher than in adjacent normal tissues (p < 0.001). In parallel, SUV39H2 exhibited a similar but more tumor-restricted expression pattern, being significantly upregulated in BRCA, CHOL, ESCA, GBM, head and neck squamous cell carcinoma (HNSC), KIRC, LIHC, LUAD, and STAD (Fig. 1 b). Notably, SUV39H2 expression was markedly elevated in testicular germ cell tumors (TGCT) and renal carcinomas, consistent with its known germline-associated and proliferative expression characteristics. Importantly, metastatic tumor samples, wherever available (such as in SKCM, UVM, and BRCA datasets), also demonstrated high expression levels of SUV39H1 and SUV39H2, suggesting their potential involvement in metastatic progression and the maintenance of chromatin reprogramming in advanced disease states (Fig. 1 a, b). Within the HNSC cohort, where HPV status was annotated, a distinct expression difference was observed: HPV-negative tumors exhibited significantly higher SUV39H1 and SUV39H2 expression compared to HPV-positive counterparts. These findings suggest that upregulation of SUV family methyltransferases may be preferentially associated with HPV-independent oncogenic pathways and potentially linked to chromatin-driven tumorigenic mechanisms in HNSC. The summary visualization (Fig. 1 c) provides an integrated overview of log₂ fold-change (log₂FC) values and adjusted significance (–log₁₀ p-adj) across tumor types for both enzymes. Overall, SUV39H1 demonstrated a more consistently high and significant upregulation across a greater number of cancer types than SUV39H2, indicating that SUV39H1 is the more ubiquitously dysregulated member of the family. In contrast, SUV39H2 exhibited stronger but more selective upregulation, particularly in germ cell, renal, and liver cancers, suggesting tissue- or lineage-specific transcriptional control. The red intensity of the log₂FC in Fig. 1 c highlights this distinction, where SUV39H1 is broadly elevated across epithelial and solid tumors, and SUV39H2 reaches its highest expression amplitude in select tumor types such as TGCT, KIRC, and LIHC. Collectively, these data establish that SUV39H1 and SUV39H2 are broadly overexpressed in human cancers, with SUV39H1 showing widespread and consistent dysregulation, while SUV39H2 displays strong but cancer-type–restricted activation. Their elevated expression in both primary and metastatic tumors, coupled with differences by HPV status, highlights their potential contribution to epigenetic reprogramming, chromatin condensation, and nuclear architectural alterations that support malignant progression. Taken together, these findings reveal distinct yet overlapping expression profiles of SUV39H1 and SUV39H2 across human cancers, emphasizing their potential oncogenic relevance and chromatin regulatory functions. To further explore the clinical implications of this dysregulation, we next assessed the prognostic significance of SUV39H1 and SUV39H2 expression across TCGA cancer types. 3.2. Prognostic significance of SUV39H1 and SUV39H2 expression across cancers To determine the clinical relevance of SUV39H1 and SUV39H2 upregulation, we next evaluated their association with overall survival (OS) and disease-free survival (DFS) across TCGA cancer cohorts. At the pan-cancer level, patients with high SUV39H1 and SUV39H2 expression showed a significant reduction in both OS and DFS compared to those with low expression (log-rank p < 0.001) (Fig. 2 a). This trend indicates that elevated expression of either methyltransferase is broadly associated with poor patient prognosis across multiple tumor types. To systematically identify cancer-specific prognostic associations, we performed univariate Cox regression analysis across 33 cancers (Fig. 2 b). The resulting heatmaps revealed that SUV39H1 overexpression was significantly associated with worse OS and DFS in cancers such as adrenocortical carcinoma (ACC), glioblastoma multiforme (GBM), sarcoma (SARC), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), and lung adenocarcinoma (LUAD) (Fig. 2 b). SUV39H2, while showing fewer associations overall, displayed notable negative prognostic impact in GBM, testicular germ cell tumor (TGCT), SARC, and ACC, highlighting its importance in specific tumor contexts (Fig. 2 b). Kaplan–Meier analyses across individual cancer types further confirmed these associations. For disease-free survival, high SUV39H1 expression predicted significantly shorter survival in ACC, KIRC, prostate adenocarcinoma (PRAD), and uterine corpus endometrial carcinoma (UCS) (Fig. 2 c). Similarly, SUV39H2 high-expression cohorts exhibited poorer DFS outcomes in ACC, GBM, SARC, and TGCT (Fig. 2 d), supporting its role in tumor relapse and progression. For overall survival, consistent trends were observed. Patients with high SUV39H1 expression had markedly reduced OS in ACC, cervical squamous cell carcinoma (CESC), skin cutaneous melanoma (SKCM), and uveal melanoma (UVM) (Fig. 2 e). Elevated SUV39H2 expression was also associated with poor OS in ACC, breast invasive carcinoma (BRCA), kidney chromophobe (KICH), LIHC, LUAD, mesothelioma (MESO), SARC, and thyroid carcinoma (THCA) (Fig. 2 f). Notably, among all tumor types, ACC, GBM, and SARC emerged as high-risk cancers where elevated expression of both SUV39H1 and SUV39H2 correlated with significantly shorter OS and DFS, suggesting cooperative or compensatory functions of these methyltransferases in promoting aggressive tumor phenotypes. Together, these findings demonstrate that SUV39H1 and SUV39H2 overexpression correlates with poor clinical outcomes across multiple cancers, with SUV39H1 exerting a more widespread prognostic impact, while SUV39H2 displays cancer-type–restricted but potent effects. These results identify the SUV39 family as independent prognostic indicators and potential epigenetic drivers of tumor progression in diverse malignancies. 3.3. SUV39H1 and SUV39H2 are upregulated in ovarian cancer and predict poor survival Given the consistent pan-cancer association of SUV39H1 and SUV39H2 with adverse prognosis, we next focused our analysis on ovarian cancer, one of the most lethal gynecological malignancies. Ovarian cancer remains the third leading cause of cancer-related death among women in India (Bray et al. 2024 ), largely due to late-stage diagnosis, extensive peritoneal metastasis, and the high rate of recurrence following chemotherapy. Among its subtypes, high-grade serous ovarian carcinoma (HGSOC) accounts for nearly 70–80% of all cases and is characterized by extensive genomic instability, frequent TP53 mutations, and widespread epigenetic dysregulation. Given the critical role of chromatin-modifying enzymes in regulating genome stability and gene expression, we hypothesized that aberrant activity of SUV39 family histone methyltransferases could contribute to the aggressive phenotype of ovarian tumors. Furthermore, gynecological malignancies often exhibit alterations in chromatin states and lamina-associated heterochromatin, making this cancer type particularly relevant to investigate the nuclear architectural functions of SUV-family enzymes. To explore this, we first analyzed the expression levels of SUV39H1 and SUV39H2 in ovarian cancer tissues compared to normal ovarian samples using the TCGA and GEO (GSE27651) datasets. In the TCGA ovarian cancer cohort, both SUV39H1 and SUV39H2 were significantly upregulated in ovarian tumor tissues compared with normal controls (p = 2.85×10⁻³⁸ and p = 1.48×10⁻⁵⁰, respectively) (Fig. 3 a, 3 b). Consistent with this, in the GSE27651 dataset, which includes normal ovarian surface epithelium (OSE, n = 6) and high-grade serous ovarian carcinoma (HGSOC, n = 22), both SUV39H1 and SUV39H2 mRNA levels were markedly elevated in HGSOC samples (****p < 0.0001) (Fig. 3 c, 3 d). These findings confirm that SUV39-family members are consistently overexpressed in ovarian cancer across independent datasets, suggesting a conserved epigenetic alteration in this malignancy. Next, to evaluate their prognostic relevance, Kaplan–Meier survival analyses were performed. As shown in Fig. 3 e, high SUV39H2 expression was significantly associated with poorer overall survival (hazard ratio [HR] = 3.27, 95% CI = 1.33–8.03; log-rank p = 0.0066), with a median survival of 30 months compared to 143 months for the low-expression group (Fig. 3 e). While SUV39H1 also showed a trend toward reduced survival in the high-expression cohort (HR = 2.36; p = 0.11), this did not reach statistical significance (Fig. 3 f), possibly due to the smaller cohort size or differential functional contribution between the two paralogs. Collectively, these results demonstrate that both SUV39H1 and SUV39H2 are transcriptionally upregulated in ovarian cancer, and that SUV39H2 expression, in particular, serves as a strong indicator of poor patient prognosis. These data highlight the SUV39 family as potential epigenetic drivers of ovarian tumorigenesis, justifying further exploration of their functional and mechanistic roles in this malignancy. Western blot analysis was performed to assess the expression levels of SUV39H2 protein across multiple ovarian cancer cell lines, including A2780, IGROV1, OVCAR3, OVCAR4, OVCAR5, and OVCAR8. Specific probing for SUV39H2 revealed that the A2780 cell line exhibited the strongest and most intense band corresponding to SUV39H2 (Fig. 3 g), indicating significantly higher protein levels compared to the other cell lines. In contrast, SUV39H1 expression was higher in IGROV1 and OVCAR4 cell lines, whereas OVCAR3 and OVCAR5 showed very faint SUV39H1 bands, indicating minimal expression (Fig. 3 g). Beta-actin, used as a loading control, was consistently expressed across all samples. These results identify A2780 as the optimal model for studying SUV39H2-related functions in ovarian cancer, as it exhibits the highest expression in this cell line. 3.4. SUV39H2-Associated Tumor-Infiltrating Lymphocyte (TIL) Infiltration in Ovarian Cancer Given the strong association between SUV39H2 overexpression and poor patient prognosis in ovarian cancer, we next sought to explore the potential mechanisms underlying this adverse clinical outcome. Tumor progression and therapy resistance in ovarian cancer are profoundly influenced by the tumor immune microenvironment (TIME), where altered chromatin landscapes can reprogram immune-related gene expression and modulate immune cell infiltration. As an epigenetic regulator, SUV39H2-mediated H3K9 trimethylation (H3K9me3) is known to promote the transcriptional silencing of genes involved in immune and inflammatory responses, thereby facilitating immune escape and tumor tolerance. To determine whether SUV39H2 expression correlates with changes in immune infiltration, we performed a comprehensive analysis using the TISIDB platform, integrating tumor-infiltrating lymphocyte (TIL) profiles with gene expression data. This analysis enabled us to assess whether the epigenetic activation of SUV39H2 contributes to an immunosuppressive phenotype in ovarian cancer. The results, detailed in the following section, reveal that high SUV39H2 expression is associated with a marked reduction in multiple T-cell, B-cell, NK-cell, and myeloid cell subsets, suggesting that SUV39H2 may actively shape an immune-excluded tumor microenvironment. 3.4.1. SUV39H2 Expression and Immune Cell Infiltration Analysis using TISIDB was performed to investigate the relationship between SUV39H2 gene expression and tumor-infiltrating lymphocyte (TIL) abundance in ovarian cancer (Fig. 4 ). Scatter plot data revealed a predominantly negative correlation between SUV39H2 expression and the infiltration levels of most immune cell types within the tumor microenvironment (Fig. 4 ). Specifically, elevated SUV39H2 expression was associated with a marked decrease in key immune populations, including central memory and effector memory CD4 + and CD8 + T cells, T helper subsets (Th1, Th17), follicular helper T cells (Tfh), regulatory T cells (Tregs), as well as immature and activated B cells (Fig. 4 ). Natural killer (NK) cells and several myeloid cells—including neutrophils, eosinophils, monocytes, and macrophages—also showed reduced infiltration concurrent with higher SUV39H2 levels. Among these, effector memory CD8 + T cells and eosinophils exhibited the strongest negative associations. Notably, two immune cell types—activated CD4 + T cells and T helper 2 (Th2) cells—demonstrated a positive correlation with SUV39H2 expression, suggesting selective immune modulation by this gene (Fig. 4 ). These findings imply that increased SUV39H2 expression may contribute to an immunosuppressive tumor microenvironment by broadly reducing the infiltration of multiple immune cell subsets, potentially facilitating tumor immune evasion in ovarian cancer. 3.4.2. SUV39H2 Methylation and Immune Cell Abundance Further analysis assessed correlations between SUV39H2 gene methylation status and TIL abundance in ovarian tumors. Methylation, which generally represses gene activity, showed weak positive trends with increased infiltration of γδ T cells (Tgd) and Th2 cells, although these associations lacked strong statistical support. Conversely, a more robust negative correlation was identified between SUV39H2 methylation and neutrophil infiltration (Fig. 5 ), indicating that higher methylation levels are linked with reduced neutrophil presence. Additional weaker negative trends were observed for effector and central memory CD8 + T cells, immature B cells, plasmacytoid dendritic cells (pDCs), immature dendritic cells (iDCs), and activated CD8 + and CD4 + T cells, as well as activated B cells (Fig. 5 ). It is essential to note that these methylation-related observations are preliminary and derived from a limited dataset of nine ovarian cancer cases, which limits their generalizability. These correlations should be interpreted cautiously, as they do not establish causality and may be influenced by other biological factors. Nonetheless, the data provide initial evidence that SUV39H2 methylation might modulate the immune landscape in ovarian tumors, with potential implications for tumor immune evasion mechanisms. Future larger-scale studies are necessary to validate and clarify the functional impact of SUV39H2 methylation on immune infiltration in ovarian cancer. 3.5. SUV39H1/2 Correlates with B-Type Lamins Across Ovarian and Pan-Cancer Cohorts Given the association of SUV39H2 overexpression with an immunosuppressive tumor microenvironment in ovarian cancer, we next examined whether these methyltransferases also influence nuclear structural components that are central to genome organization and chromatin stability. Since lamins, particularly Lamin B1 (LMNB1) and Lamin B2 (LMNB2), are key determinants of nuclear architecture and heterochromatin anchoring at the nuclear periphery and were also largely upregulated in multiple cancers (Kundu et al. 2025 ), we investigated potential transcriptional correlations between SUV39 family enzymes and lamin genes across ovarian cancer and a Pan-Cancer cohort. Correlation analyses revealed moderate to strong positive associations between SUV39H1 and SUV39H2, and B-type lamins (LMNB1 and LMNB2), suggesting a coordinated regulatory relationship (Fig. 6 a, b). In ovarian cancer, SUV39H2 expression correlated with LMNB1 (R = 0.49) and LMNB2 (R = 0.42), while SUV39H1 displayed similar correlations (R = 0.40 and R = 0.39, respectively) (Fig. 6 e, f). These associations were further strengthened in the Pan-Cancer dataset, where SUV39H2 correlated with LMNB1 (R = 0.56) and LMNB2 (R = 0.47), and SUV39H1 with LMNB1 (R = 0.56) and LMNB2 (R = 0.52) (Fig. 6 c, d). These consistent patterns across multiple cancer types suggest a conserved functional linkage between SUV39 enzymes and B-type lamins in maintaining nuclear organization during tumorigenesis. In contrast, LMNA, which encodes Lamin A/C, showed weak or negligible correlations with both methyltransferases. In ovarian cancer, SUV39H2 and LMNA exhibited a slight negative correlation (R = − 0.098) (Fig. 6 e), while correlations in the Pan-Cancer cohort were minimal (SUV39H2: R = − 0.02; SUV39H1: R = 0.15) (Fig. 6 c, d). Importantly, Lamin A expression is typically downregulated in several cancer types, including breast, colorectal, and ovarian malignancies, where its reduced levels are linked to increased nuclear deformability, metastatic dissemination, and poor prognosis. Conversely, higher Lamin A expression has been associated with improved patient survival and more differentiated tumor phenotypes, underscoring its potential as a tumor suppressor. Given that SUV39H1 and SUV39H2 catalyze H3K9 trimethylation (H3K9me3) to promote heterochromatin formation and gene silencing, the observed inverse trend between SUV39 expression and Lamin A suggests that Lamin A may be a downstream target of SUV39H1/H2-mediated epigenetic repression. Such regulation could facilitate chromatin compaction and nuclear architectural remodeling, enabling tumor cells to adopt more plastic and aggressive phenotypes. Functionally, the positive association of SUV39H1/2 with B-type lamins implies a cooperative role in preserving repressive nuclear organization. In contrast, the negative association with Lamin A/C highlights a potential mechanism by which SUV39 overexpression contributes to the loss of nuclear rigidity and increased tumor adaptability. In summary, these results reveal a robust co-expression relationship between SUV39H1/2 and B-type lamins (LMNB1, LMNB2) across ovarian and other cancers, suggesting a coordinated role in maintaining nuclear structural integrity and heterochromatin repression. Conversely, the suppression of Lamin A/C expression by SUV39H1/2 may represent an adaptive mechanism that enhances malignant progression by promoting nuclear deformability and epigenetic plasticity. 3.6. Chaetocin-Mediated Inhibition of SUV39H2 Upregulates Lamin A in Ovarian Cancer Cells Building upon the observed negative correlation between SUV39H family members and A-type lamins, we next sought to validate whether SUV39H2 activity directly influences nuclear lamina components experimentally. To this end, ovarian cancer A2780 cells were treated with chaetocin, a fungal metabolite and an inhibitor of SUV39H1/2, at concentrations of 300 nM and 600 nM, followed by assessment of Lamin A and Lamin C expression. Western blot analysis revealed a dose-dependent upregulation of Lamin A/C following pharmacological inhibition of SUV39H2 using chaetocin in A2780 ovarian cancer cells. Lamin A expression remained largely unchanged at 300 nM chaetocin, whereas a statistically significant increase was observed at 600 nM, indicating that suppression of SUV39H2 enzymatic activity enhances Lamin A expression (Fig. 7 a, b). Similarly, Lamin C exhibited a comparable expression pattern, with a modest elevation at 300 nM and a marked induction at 600 nM chaetocin, suggesting that SUV39H2 inhibition derepresses Lamin A/C expression (Fig. 7 a, b). These findings support a potential epigenetic regulatory link between SUV39H2 activity and Lamin A/C expression, wherein SUV39H2 may act as a negative modulator of LMNA transcription or stability, thereby influencing nuclear structure and cancer cell phenotype. Immunofluorescence microscopy further corroborated these findings. Untreated A2780 cells exhibited the characteristic ring-like peripheral localization of Lamin A, consistent with its nuclear envelope distribution. Following 600 nM Chaetocin treatment, the intensity of Lamin A staining was visibly enhanced, with quantitative analysis confirming a significant increase (p < 0.01) in fluorescence intensity relative to the controls (Fig. 7 c, d). Notably, the nuclear localization pattern remained intact, indicating that the observed increase reflects elevated protein expression rather than mislocalization or structural disruption. Line-scan analysis further confirmed these findings and also revealed differences in the intensity of lamin A across the nuclear periphery, suggesting an observed increase in lamin A protein expression in SUV39h1/h2-inhibited cells (Fig. 7 d). Collectively, these results demonstrate that inhibition of SUV39H2 leads to upregulation of Lamin A in ovarian cancer cells, suggesting a regulatory axis between SUV39H2-mediated histone methylation and nuclear lamina integrity. The dose-dependent and isoform-specific effects observed for Lamin A and Lamin C highlight the complex interplay between epigenetic enzymes and structural nuclear proteins, providing mechanistic insight into how SUV39H2 may contribute to nuclear architecture remodeling and tumor progression. 4. Discussion SUV39H1 and SUV39H2, the two canonical H3K9 trimethyltransferases, are central to the establishment and maintenance of transcriptionally repressive heterochromatin (Peters et al.,2001). By catalyzing the trimethylation of histone H3 lysine 9 (H3K9me3), these enzymes enforce epigenetic silencing of gene expression, preserve genomic integrity, and sustain higher-order chromatin organization (Rea et al. 2000 ). Although their roles in heterochromatin formation and genome stability are well established, their cancer-specific functions and interplay with structural nuclear components remain insufficiently understood. Recent evidence has begun to reveal that these methyltransferases not only regulate gene expression but also influence tumor cell plasticity, immune evasion, and nuclear morphology, which are hallmarks that define malignant progression (Li et al.,2025). In this study, we provide a comprehensive multidimensional analysis of SUV39H1 and SUV39H2 across human cancers, integrating transcriptomic, prognostic, immune infiltration, methylation, and structural correlation data. Our findings reveal distinct yet overlapping oncogenic landscapes for these enzymes, positioning them as key epigenetic regulators at the interface between chromatin state, immune modulation, and nuclear architecture. Our comprehensive analysis reveals that SUV39H2 is broadly overexpressed across multiple human cancers, including acute myeloid leukemia (AML), breast, colon, esophageal, lung, ovarian, prostate, stomach, and endometrial cancers. Particularly striking is its marked upregulation in AML and testicular tumors, where the difference between normal and tumor tissues underscores its potential as a diagnostic biomarker. The restricted expression of SUV39H2 in normal tissues, in contrast to its pronounced elevation in tumor contexts, underscores its therapeutic promise as a tumor-selective target. Given its role in epigenetic repression, it is plausible that SUV39H2 drives oncogenesis through silencing of tumor suppressor genes, promoting dedifferentiation, and sustaining cellular plasticity. Similarly, SUV39H1 exhibits significant upregulation in several cancer types, including AML, breast, colon, liver, lung, and testicular cancers. In AML, its strong expression suggests a function in preserving the undifferentiated state of leukemic blasts through persistent repressive chromatin programming (Chakraborty et al.,2003). In contrast, its moderate upregulation in prostate, esophageal, pancreatic, and rectal cancers suggests a supportive or secondary role in tumor progression. Notably, SUV39H1 expression remains low in renal and thyroid cancers, highlighting the context-dependent nature of its oncogenic potential and suggesting the existence of lineage-specific epigenetic dependencies. A key finding of this study is the robust prognostic relevance of SUV39H1 and SUV39H2 in high-grade serous ovarian cancer (HGSOC). Both genes are significantly overexpressed in tumor tissues relative to normal ovarian surface epithelium, but SUV39H2 stands out as a particularly strong predictor of poor patient outcomes. High SUV39H2 expression correlates with a median overall survival of 30 months compared to 143 months in the low-expression cohort, with a hazard ratio of 3.27, establishing it as a potent negative prognostic biomarker. Although SUV39H1 shows a similar pattern, its prognostic strength is comparatively lower. These data implicate SUV39H2 as a key driver of aggressive disease behavior in HGSOC, potentially by enforcing epigenetic silencing of immune-modulatory or differentiation-related genes, thereby fostering immune evasion and maintaining malignant plasticity (Saha and Muntean 2021 ). Immune infiltration analyses further support the immunosuppressive role of SUV39H2. Its high expression negatively correlates with the abundance of multiple immune effector subsets, including effector memory CD8⁺ T cells, regulatory T cells, B cells, NK cells, and myeloid-derived cells. This immune-exclusion phenotype suggests that SUV39H2 may actively remodel the chromatin landscape of immune-regulatory genes to dampen anti-tumor immune responses. Interestingly, a positive association with Th2 and activated CD4⁺ T cells was observed, indicative of a shift toward an immunosuppressive tumor microenvironment. Furthermore, the inverse relationship between SUV39H2 promoter methylation and immune infiltration, particularly involving neutrophils and plasmacytoid dendritic cells, implies that DNA methylation–dependent regulation of SUV39H2 may fine-tune its immunomodulatory impact, potentially establishing a feedback circuit that reinforces immune escape. Another important insight from this study is the discovery of a positive correlation between SUV39H1/H2 expression and nuclear lamina components specifically B-type lamins i.e. LMNB1 and LMNB2. Lamin B proteins are structural determinants of nuclear integrity and play crucial roles in heterochromatin tethering and spatial genome organization (Dechat et al. 2008 , 2009 ; van Steensel and Belmont 2017 ; Sobo et al. 2024 ). We have previously shown that B-type lamin expression in strongly associated with cancer progression (Kundu et al. 2025 ). The co-expression pattern btween B-type lamins and SUV39H1/H2 enzymes observed in this study suggests that SUV39 enzymes may cooperate with Lamin B to maintain nuclear architecture and chromatin compartmentalization in cancer cells. This relationship may reflect a functional axis wherein SUV39-mediated H3K9me3 deposition stabilizes peripheral heterochromatin domains in coordination with Lamin B, thereby promoting a transcriptionally repressive nuclear environment that favors tumor cell survival and adaptation (Harr et al. 2015 ). In contrast, Lamin A (LMNA) exhibits an inverse relationship with SUV39H1 and SUV39H2, suggesting a differential regulatory paradigm. LMNA is often downregulated in cancers (Chiarini et al. 2022a ; Kundu et al. 2025 ), and its loss has been associated with increased nuclear deformability, enhanced proliferation, and metastatic dissemination (Bell et al. 2022 ). The observed negative correlation thus suggests that SUV39 enzymes might epigenetically repress LMNA expression, contributing to structural and mechanical alterations that facilitate tumor aggressiveness. Experimental validation using the SUV39H2 inhibitor chaetocin further substantiates this hypothesis. Treatment of A2780 ovarian cancer cells with chaetocin resulted in a clear restoration of Lamin A protein levels, particularly those localized at the nuclear envelope, as confirmed by both immunofluorescence and Western blot analysis. This restoration suggests that SUV39H2 represses LMNA transcription through H3K9me3-mediated silencing and that its inhibition can reverse this repression. Considering the established tumor-suppressive roles of Lamin A, the reactivation of LMNA upon SUV39H2 inhibition suggests a potential therapeutic strategy in which targeting SUV39H2 could restore nuclear architecture integrity and re-establish anti-oncogenic mechanical constraints. Given that Lamin A deficiency contributes to enhanced cellular plasticity and invasiveness, SUV39H2 inhibition may not only attenuate tumor growth but also limit metastatic potential by reprogramming nuclear organization (Chiarini et al. 2022b ). In summary, this study elucidates the multifaceted role of SUV39H1 and SUV39H2 in cancer progression, extending beyond canonical chromatin repression to encompass immune modulation and nuclear structural regulation. SUV39H2, in particular, emerges as a key oncogenic epigenetic effector and prognostic marker, especially in ovarian cancer. Its strong association with immune exclusion and Lamin B enrichment, coupled with suppression of Lamin A, highlights its dual role in reconfiguring both the transcriptional and structural landscapes of cancer cells. These findings position SUV39H2 not only as a biomarker of poor prognosis but also as a promising therapeutic target for re-establishing tumor-suppressive chromatin and nuclear architecture. Further mechanistic and translational studies are warranted to elucidate how SUV39H2 integrates with Lamin-mediated nuclear scaffolding and immune evasion pathways, thereby opening new avenues for precision epigenetic therapy in malignancies characterized by SUV39H2 overexpression. Declarations Declaration of Interest The authors report no financial or non-financial conflicts of interest. Clinical trial number Not applicable. Funding The work was supported by grants from the Science and Engineering Research Board, Department of Science and Technology (DST-SERB), Government of India, with grant number ECR/2016/001740 and AIIMS intramural funding. SK, thanks to the University Grants Commission, India, for fellowship support. Author Contribution SK was involved in conceptualisation, visualization, methodology, data analysis, data interpretation, manuscript writing, editing, and reviewing; AR was involved in manuscript writing, reviewing, and editing, conducting experiments; AK and AS were involved in manuscript writing, reviewing, editing, supervision, and funding acquisition. Acknowledgement The authors thank Prof. Adam R Karpf, Nebraska Medical Center, Omaha, USA, for providing ovarian cancer cell lines as a generous gift. The authors thank the All India Institute of Medical Sciences, New Delhi, India, for providing all necessary support. The authors thank the Confocal Microscopy Facility, Centralized Core Research Facility, AIIMS, New Delhi, for their assistance with confocal image acquisition and analysis. 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19:04:39","extension":"xml","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":121606,"visible":true,"origin":"","legend":"","description":"","filename":"cadddc39130e49deb98e0346ac2dca841structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/f8d14efa39c5cea4fd2c86f4.xml"},{"id":97920770,"identity":"01b6f6c6-efae-4123-a329-4bf3bf24121c","added_by":"auto","created_at":"2025-12-10 19:04:39","extension":"html","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":132650,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/589376ec6f7523e64f625005.html"},{"id":98421385,"identity":"3ba0f23a-d4f5-41d0-88dd-5943cb06cd54","added_by":"auto","created_at":"2025-12-17 16:27:02","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1033144,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePan-cancer expression profile of SUV39H1 and SUV39H2 across TCGA tumor types.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003eExpression pattern of \u003cem\u003eSUV39H1\u003c/em\u003e (log₂ TPM) across 33 tumor types from The Cancer Genome Atlas (TCGA). Red dots represent tumor tissues, and blue dots represent matched normal tissues; \u003cstrong\u003e(b)\u003c/strong\u003e Expression pattern of \u003cem\u003eSUV39H2\u003c/em\u003e(log₂ TPM) across the same TCGA cancer types; \u003cstrong\u003e(c)\u003c/strong\u003e Bubble plot summarizing differential expression analysis of \u003cem\u003eSUV39H1\u003c/em\u003e and \u003cem\u003eSUV39H2\u003c/em\u003ebetween tumor and normal tissues. Bubble size corresponds to adjusted p-value (−log₁₀ FDR), and color scale represents the magnitude of log₂ fold change. Both enzymes exhibit strong and significant upregulation in several tumor types, highlighting their broad oncogenic potential and tissue-specific expression differences. [Statistical significance: \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05 (*\u003cem\u003e), p \u0026lt; 0.01 (**), p \u0026lt; 0.001 (***\u003c/em\u003e)].\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/55d52e359af6d2e66e09902f.jpg"},{"id":98421308,"identity":"7436ef66-fd92-4415-9a24-936888ed74c5","added_by":"auto","created_at":"2025-12-17 16:26:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1397309,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrognostic significance of SUV39H1 and SUV39H2 expression across Pan cancers.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003eKaplan–Meier survival curves showing the association of combined SUV39H1 and SUV39H2 expression with overall survival (left) and disease-free survival (right) across the pan-cancer cohort. Patients with high SUV39H1/H2 expression (red) exhibit significantly reduced survival compared to those with low expression (blue); \u003cstrong\u003e(b)\u003c/strong\u003e Heatmap summarizing the prognostic impact of SUV39H1 and SUV39H2 expression across 33 TCGA cancer types. Each cell represents the log₂ hazard ratio (HR) for either overall survival (OS) or disease-free survival (DFS), with color intensity indicating the magnitude and direction of association. Red shades denote higher risk (HR \u0026gt; 1) and blue shades indicate protective effects (HR \u0026lt; 1). Red and Blue boundaries represent statistical significance (logrank \u003cem\u003ep \u003c/em\u003e\u0026lt; 0.05); \u003cstrong\u003e(c–d)\u003c/strong\u003eDisease-free survival (DFS) analysis of SUV39H2 (\u003cstrong\u003ec\u003c/strong\u003e) and SUV39H1 (\u003cstrong\u003ed\u003c/strong\u003e) in representative tumor types, including adrenocortical carcinoma (ACC), kidney renal papillary cell carcinoma (KIRP), prostate adenocarcinoma (PRAD), uterine carcinosarcoma (UCS), glioblastoma multiforme (GBM), sarcoma (SARC), and testicular germ cell tumor (TGCT). High expression of SUV39H2 and SUV39H1 is significantly associated with reduced DFS in multiple cancer types, supporting their role in tumor progression; \u003cstrong\u003e(e–f)\u003c/strong\u003e Overall survival (OS) analysis of SUV39H2 (\u003cstrong\u003ee\u003c/strong\u003e) and SUV39H1 (\u003cstrong\u003ef\u003c/strong\u003e) across selected cancers. Elevated SUV39H2 expression predicts poor OS in ACC, cervical squamous cell carcinoma (CESC), skin cutaneous melanoma (SKCM), and uveal melanoma (UVM), while SUV39H1 overexpression correlates with reduced OS in ACC, breast carcinoma (BRCA), kidney chromophobe (KICH), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), mesothelioma (MESO), sarcoma (SARC), and thyroid carcinoma (THCA).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/0ab862c6a6fed70a00642308.jpg"},{"id":97920750,"identity":"e010693a-8192-4883-8bc5-eaeabde60817","added_by":"auto","created_at":"2025-12-10 19:04:39","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":371768,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExpression profile and prognostic outcome of SUV39H1 and SUV39H2 in ovarian cancer.\u003c/strong\u003e(\u003cstrong\u003ea\u003c/strong\u003e) Gene expression of SUV39H1 in ovarian tumor compared to normal ovary analyzed from TCGA datasets through TNMplot webtool; (\u003cstrong\u003eb\u003c/strong\u003e) Gene expression of SUV39H2 in ovarian tumor compared to normal ovary analyzed from TCGA datasets through TNMplot webtool; (\u003cstrong\u003ec-d\u003c/strong\u003e) Gene expression of SUV39H2 and SUV39H, respectively, in HGSOC compared to Normal OSE analyzed by utilizing GEO data with accession no. GSE27651; (\u003cstrong\u003ee-f\u003c/strong\u003e) Overall Survival of patients with high and low expression cohorts of SUV39H2 and SUV39H1, respectively, from the GEO dataset with accession no. GSE27651; (\u003cstrong\u003eg\u003c/strong\u003e) Western blot images showing SUV39H2 and SUV39H1 expression across A2780, IGROV1, OVCAR3, OVCAR4, OVCAR5, and OVCAR8 cell lines. Beta-actin was used as a loading control [The uncropped raw images are shown in Fig. S1 (supplementary information file)].\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/a87eb8f1d29bc045efa422c3.jpg"},{"id":98422120,"identity":"5e25d7ec-58bb-462d-8bc9-a05a05628695","added_by":"auto","created_at":"2025-12-17 16:30:29","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":627135,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation Between SUV39H2 Expression and Tumor-Infiltrating Lymphocyte (TIL) Abundance in Ovarian Cancer. \u003c/strong\u003eScatter plots derived from TISIDB analysis illustrate the relationship between SUV39H2 gene expression and the infiltration levels of various immune cell types in ovarian cancer tumors. Most immune cell populations, including central memory and effector memory CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e T cells, Th1, Th17, Tfh, Tregs, immature and activated B cells, NK cells, and myeloid cells such as neutrophils and eosinophils, show a significant negative correlation with SUV39H2 expression. Notably, activated CD4\u003csup\u003e+\u003c/sup\u003e T cells and Th2 cells display a positive correlation. These data suggest that elevated SUV39H2 expression is broadly associated with diminished immune cell infiltration, potentially contributing to immune suppression in the tumor microenvironment.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/7c1995de553ab24c175ca546.jpg"},{"id":98422122,"identity":"8d0fe3b4-a784-4c83-b08a-a61a675a73cb","added_by":"auto","created_at":"2025-12-17 16:30:29","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":330503,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelationship Between SUV39H2 Methylation and Tumor-Infiltrating Lymphocyte (TIL) Abundance in Ovarian Cancer.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eScatter plots from TISIDB analysis demonstrate the correlations between SUV39H2 gene methylation levels and infiltration of immune cells in ovarian cancer tumors. Increased methylation of SUV39H2 is significantly associated with decreased neutrophil infiltration. Weaker negative trends are observed for effector and central memory CD8\u003csup\u003e+\u003c/sup\u003e T cells, immature B cells, plasmacytoid and immature dendritic cells, as well as activated CD8\u003csup\u003e+\u003c/sup\u003e, CD4\u003csup\u003e+\u003c/sup\u003e T cells, and B cells. Mild positive trends with gamma delta T cells and Th2 cells are also observed, although these findings lack strong statistical support. Due to the limited sample size (n = 9), these preliminary findings warrant further investigation to elucidate the role of SUV39H2 methylation in modulating tumor immune infiltration.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/4058eee8b786c0f14a3b5dbf.jpg"},{"id":98421442,"identity":"78611243-caeb-4466-806f-624b190e1b6d","added_by":"auto","created_at":"2025-12-17 16:27:23","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":721944,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between SUV39H1/SUV39H2 expression and Lamin genes (LMNA, LMNB1, LMNB2) across cancers.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003eHeatmap showing the Spearman correlation between SUV39H2 expression and LMNA, LMNB1, and LMNB2 gene across 33 TCGA cancer types. Each square represents the strength and direction of correlation (Spearman’s ρ), with red indicating a positive and blue indicating a negative correlation. Significant correlations (p ≤ 0.05) are shown with filled squares, while non-significant correlations (p \u0026gt; 0.05) are marked with a cross; \u003cstrong\u003e(b)\u003c/strong\u003e Heatmap depicting the correlation between SUV39H1 expression and LMNA, LMNB1, and LMNB2 levels across the same cancer types, showing a broadly similar positive correlation trend as SUV39H2; \u003cstrong\u003e(c)\u003c/strong\u003e Scatter plots showing significant positive correlations between SUV39H2 expression and LMNB1 (R = 0.56, p = 0), LMNB2 (R = 0.47, p = 0), and a weak, non-significant correlation with LMNA (R = 0.05, p = 0.053) across pan-cancer TCGA data; (d) Scatter plots showing SUV39H1 correlation with LMNB1 (R = 0.56, p = 0), LMNB2 (R = 0.52, p = 0), and LMNA (R = 0.15, p = 0) across the TCGA pan-cancer dataset; (e–f) Scatter plots showing tumor-specific correlation patterns between SUV39H2 (e) and SUV39H1 (f) with Lamin genes in ovarian cancer (OV). Both SUV39H1 and SUV39H2 show strong positive associations with LMNB1 and LMNB2 expression (R = 0.39–0.49, p \u0026lt; 0.001), while correlations with LMNA are weak or non-significant.\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/3e6833ab0380a06399edffdd.jpg"},{"id":97920757,"identity":"a4b1eb90-3045-47a1-b212-6d2204895d49","added_by":"auto","created_at":"2025-12-10 19:04:39","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":532828,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSUV39H2 inhibition by chaetocin upregulates Lamin A expression in ovarian cancer cells.\u003c/strong\u003e(\u003cstrong\u003ea\u003c/strong\u003e) Western blot images of Lamin A, Lamin C, and beta-actin in A2780 cells treated with chaetocin (300 nM and 600 nM) compared to untreated controls. Beta actin serves as loading control [The uncropped raw images are shown in Fig. S2 (supplementary information file)]; (\u003cstrong\u003eb\u003c/strong\u003e) Bar graphs representing densitometric quantification of Lamin A and Lamin C expression normalized to beta-actin. A significant increase in Lamin A expression is observed at 600 nM Chaetocin (*p \u0026lt; 0.05). Lamin C shows a significant decrease at 300 nM and a highly significant increase at 600 nM treatment (****p \u0026lt; 0.0001), indicating dose-dependent effects; (\u003cstrong\u003ec\u003c/strong\u003e) Fluorescence Microscopy of Lamin A in A2780 Cells Treated with Chaetocin. Representative fluorescence microscopy images showing Lamin A (green) and nuclear DNA (DAPI, blue) in untreated A2780 cells and cells treated with 600 nM chaetocin. Lamin A is localized at the nuclear periphery in both conditions, with increased intensity in treated cells; (\u003cstrong\u003ed\u003c/strong\u003e) Line-scan analysis and respective intensity profile plot of lamin A across the nucleus in untreated and chaetocin-treated A2780 cell lines, showing that chaetocin treatment increases the intensity of lamin A at the nuclear periphery.\u003c/p\u003e","description":"","filename":"Figure7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/e359b42f114968ec51c15d1c.jpg"},{"id":106808997,"identity":"0393c7f8-0594-47b3-81dd-ce577a378e73","added_by":"auto","created_at":"2026-04-13 16:05:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6368320,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/24da46ba-8213-463b-a0bd-98a44f8b413e.pdf"},{"id":98421650,"identity":"7a0e6f10-3057-46e5-9f4b-baa85631ec7c","added_by":"auto","created_at":"2025-12-17 16:28:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":302943,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformationFile.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8137620/v1/2f30e6eceffc9d17992f24cd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"SUV Family Histone Methyltransferases Modulate Nuclear Lamin A and Drive Tumorigenesis: Integrative Pan-Cancer TCGA analysis and Experimental Evidence","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eEpigenetic modifications play a central role in regulating chromatin structure, transcriptional dynamics, and genome stability (Bannister and Kouzarides \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Allis and Jenuwein \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Among the diverse set of chromatin-modifying enzymes, histone lysine methyltransferases (KMTs) establish and maintain transcriptionally permissive or repressive chromatin states by depositing specific methyl groups on histone tails (Black et al, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Husmann \u0026amp; Gozani,2019). One of the most critical histone modifications associated with transcriptional repression is the trimethylation of histone H3 at lysine 9 (H3K9me3). This repressive mark is enriched in constitutive heterochromatin regions, repetitive DNA elements, and lamina-associated domains (LADs), thereby contributing to nuclear compartmentalization, gene silencing, and chromosomal integrity (Saksouk et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Becker et al.,2016). The establishment of this mark is largely mediated by the Suppressor of Variegation (SUV) family of histone methyltransferases, which includes SUV39H1, SUV39H2, and closely related enzymes (Peters et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2001\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe SUV family is evolutionarily conserved and has been studied extensively for its role in heterochromatin formation. SUV39H1 was initially identified in \u003cem\u003eDrosophila\u003c/em\u003e as a key regulator of position-effect variegation (Elgin and Reuter \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2013\u003c/span\u003e) and later shown in mammals to be the principal enzyme responsible for catalyzing H3K9me3 at pericentric heterochromatin (Padeken et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). SUV39H2, although less well-characterized, exhibits similar catalytic activity and cooperates with SUV39H1 in establishing heterochromatin domains, particularly during development and germline specification (Weirich et al.,2021). Both enzymes act as epigenetic scaffolds, recruiting heterochromatin protein 1 (HP1) and interacting with nuclear lamina components, thereby linking chromatin compaction to nuclear architecture (Maison and Almouzni \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Collectively, the SUV family ensures the maintenance of silent chromatin, suppresses transposable elements, and stabilizes the three-dimensional nuclear landscape.\u003c/p\u003e\u003cp\u003eIncreasing evidence suggests that the deregulation of SUV family enzymes contributes to cancer biology (Li et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Saha and Muntean,2021). Aberrant SUV39H1 expression has been reported in a wide range of tumors, including kidney (Wang et al. \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), liver (Zhang et al. \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2023a\u003c/span\u003e), breast (Huang et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), brain (Li et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), and haematological cancers (Devin et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Zhang et al. \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2023b\u003c/span\u003e), where it promotes tumor cell survival through silencing of tumor suppressor genes, facilitating DNA repair evasion, and fostering an immunosuppressive microenvironment. In parallel, SUV39H2 has been shown to stabilize oncogenic transcriptional programs, inhibit apoptosis, and maintain stem-like properties in cancer cells (Li et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Importantly, alterations in SUV enzyme activity are often coupled with global changes in heterochromatin distribution and nuclear morphology \u0026mdash; features frequently observed in aggressive cancers. Recent studies have further highlighted their involvement in chemoresistance (Wang et al.,2019), underscoring the clinical relevance of targeting SUV family members in oncology.\u003c/p\u003e\u003cp\u003eDespite these insights, our understanding of the pan-cancer role of SUV family histone methyltransferases remains limited. Most studies to date have focused on individual tumor types, yielding fragmented insights into their oncogenic potential. Moreover, while SUV enzymes are strongly linked to heterochromatin formation and nuclear architecture, their relationship with nuclear lamina proteins, such as lamin A, and their contribution to large-scale nuclear reorganization in cancer, remain poorly defined. A comprehensive assessment of their expression patterns, prognostic significance, and molecular associations across diverse cancer types has not been undertaken.\u003c/p\u003e\u003cp\u003eTo address this gap, we conducted an integrated pan-cancer analysis of the Cancer Genome Atlas (TCGA) dataset to evaluate the SUV family of histone methyltransferases systematically. By analyzing their expression across multiple tumor types, investigating their prognostic impact, and exploring their association with nuclear architecture\u0026ndash;related pathways, we provide the first large-scale evidence of how SUV enzymes contribute to tumorigenesis in a pan-cancer context. Our findings not only highlight their importance as epigenetic drivers of cancer but also open new avenues for exploring SUV family members as potential biomarkers and therapeutic targets in precision oncology.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Mammalian cell culture and drug treatment:\u003c/h2\u003e\u003cp\u003eIn this study, High-grade serous ovarian cancer (HGSOC) cell lines, namely A2780, IGROV1, OVCAR3, OVCAR4, OVCAR5, and OVCAR8, were used. All cell lines were obtained from the American Type Culture Collection (ATCC), which was generously gifted by Prof. Adam R. Karpf, University of Nebraska Medical Center, Omaha, USA, and maintained according to the following protocol. Cells were cultured in RPMI 1640 medium supplemented with 10% FBS and 1% antibiotic and antimycotic solution and incubated in a humidified chamber at 37\u0026ordm;C in the presence of 5% CO\u003csub\u003e2\u003c/sub\u003e. For drug treatment, chaetocin, a Suv39h2/h2 blocker, was used. Cells were seeded at a density of 3\u0026times;10\u003csup\u003e5\u003c/sup\u003e cells in a 60mm cell culture plate. Chaetocin treatment was administered to the A2780 cell line at final concentrations of 300 nM and 600 nM from a 1mg/ml stock solution and incubated for 24 hours in a humidified chamber at 37\u0026deg;C in the presence of 5% CO\u003csub\u003e2\u003c/sub\u003e. Protein samples were collected after 24 hours of treatment.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Western blotting:\u003c/h2\u003e\u003cp\u003eWestern blotting was performed to evaluate the expression of SUV39H1 and SUV39H2 across ovarian cancer cell lines (A2780, IGROV1, OVCAR3, OVCAR4, OVCAR5, OVCAR8) and to assess Lamin A protein levels following Chaetocin treatment in A2780 cells. Cells were cultured in 60 mm tissue culture dishes using RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% antibiotic-antimycotic solution, maintained at 37\u0026deg;C in a humidified 5% CO₂ incubator. When cultures reached approximately 70\u0026ndash;80% confluence or after 24 hours of Chaetocin treatment (300 nM and 600 nM), cells were harvested by scraping in ice-cold PBS and lysed using RIPA buffer (50 mM Tris-HCl, pH 7.4; 150 mM NaCl; 1% NP-40; 0.5% sodium deoxycholate; 0.1% SDS) supplemented with protease and phosphatase inhibitor cocktails. Lysates were incubated on ice for 30 minutes with intermittent vortexing, followed by centrifugation at 14,000 rpm for 15 minutes at 4\u0026deg;C to remove cellular debris.\u003c/p\u003e\u003cp\u003eThe supernatants were collected, and protein concentrations were determined using the Bradford assay (Bio-Rad). Equal amounts of total protein (30 \u0026micro;g) were mixed with 4\u0026times; Laemmli sample buffer, boiled at 95\u0026deg;C for 5 minutes, and separated by SDS-PAGE on 10\u0026ndash;12% polyacrylamide gels. Proteins were electro-transferred onto PVDF membranes (Millipore). Membranes were blocked with 5% BSA in TBST (20 mM Tris-HCl, 150 mM NaCl, 0.1% Tween-20) for 1 hour at room temperature and incubated overnight at 4\u0026deg;C with primary antibodies against SUV39H1 (Abcam, ab12405, 1:1000), SUV39H2 (Abcam, ab184500, 1:1000), and Lamin A/C (Cell Signaling Technology, #4777, 1:2000). After washing, membranes were incubated with HRP-conjugated secondary antibodies (1:5000) for 1 hour at room temperature. Protein bands were visualized using enhanced chemiluminescence (ECL) detection reagent (Biorad) and imaged with a ChemiDoc imaging system (GE). β-actin (Cell Signaling Technology, #4970, 1:5000) served as the loading control. Densitometric quantification of protein bands was performed using ImageJ software, and relative expression levels were normalized to β-actin.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Immunofluorescence and confocal microscopy imaging:\u003c/h2\u003e\u003cp\u003eA2780 ovarian cancer cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin at 37\u0026deg;C in a humidified atmosphere containing 5% CO₂. Cells were seeded into 8-well chambered slide and treated with chaetocin (600 nM) for 24 hours. Following treatment, cells were fixed with 4% paraformaldehyde for 10 minutes at room temperature and then permeabilized with 0.1% Triton X-100 in PBS for an additional 10 minutes. After blocking with 5% normal goat serum for 1 hour, cells were incubated overnight at 4\u0026deg;C with anti-Lamin A antibody (Abcam, 1:200 dilution). The next day, cells were washed and incubated with Alexa Fluor 488-conjugated secondary antibody (Invitrogen, 1:600) for 1 hour at room temperature, followed by nuclear counterstaining with DAPI (0.5 \u0026micro;g/mL). Coverslips were mounted with Vectashield Antifade Mounting Medium (Vector Laboratories) and imaged using a Zeiss LSM 980 confocal microscope, with identical acquisition settings applied to all samples. Mid-optical sections of the confocal Z-stack images are shown in the figures.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. In silico gene expression analysis of SUV39H1 and SUV39H2 from TCGA datasets:\u003c/h2\u003e\u003cp\u003eThe mRNA expression analysis for the SUV39H1 and SUV39H2 genes in the pan-cancer model was analysed using TCGA RNA-sequencing datasets through the TIMER2.0 [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://compbio.cn/timer2/\u003c/span\u003e\u003cspan address=\"https://compbio.cn/timer2/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e] webtool (Li et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Pan-cancer dot matrix for SUV39H1 and SUV39H2 were calculated using TCGA data through TNMplot web tool [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://tnmplot.com](Bartha and Győrffy 2021\u003c/span\u003e\u003cspan address=\"https://tnmplot.com](Bartha and Győrffy 2021\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The mRNA expression of SUV39H1 and SUV39H2 was further analyzed in ovarian cancer samples using microarray gene expression datasets from the Gene Expression Omnibus (GEO) database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/geo/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/geo/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), with the accession number GSE27651. Briefly, datasets were analyzed using the GEO2R web tool, and samples were classified into Normal (N\u0026thinsp;=\u0026thinsp;6) and High-grade serous ovarian carcinoma (N\u0026thinsp;=\u0026thinsp;19) based on metadata from the submission associated with GSE27651. Gene expression (Transcripts per Million) for SUV39H1 and SUV39H2 was extracted and plotted using GraphPad PRISM software, and P-values were calculated using the Mann-Whitney t-test.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5. Survival analysis:\u003c/h2\u003e\u003cp\u003eIn this study, survival analysis was employed to investigate the relationship between SUV39H1 and SUV39H2 expression and patient outcomes. Overall survival (OS) was defined as the time from initial cancer diagnosis to the date of death from any cause. Disease-free survival (DFS) was defined as the duration following treatment completion during which patients exhibited no clinical or radiological evidence of disease recurrence.\u003c/p\u003e\u003cp\u003eThe GEPIA2 web tool (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://gepia2.cancer-pku.cn/\u003c/span\u003e\u003cspan address=\"http://gepia2.cancer-pku.cn/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) was utilized to conduct these analyses (Tang et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Li et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Patient cohorts were stratified based on SUV39H1 or SUV39H2 mRNA expression levels, specifically comparing a group exhibiting high expression of SUV39H1 or SUV39H2 to a group with low expression of these genes. The statistical significance was calculated using the log-rank test.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6. Tumor Infiltrating Lymphocyte (TIL) Analysis using TCGA RNA-seq data:\u003c/h2\u003e\u003cp\u003eTo understand the relationship between SUV39H2 gene expression/promoter methylation and the presence of tumor-infiltrating lymphocytes (TILs), the TISIDB webtool [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://cis.hku.hk/TISIDB/index.php\u003c/span\u003e\u003cspan address=\"http://cis.hku.hk/TISIDB/index.php\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (Ru et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2019\u003c/span\u003e)] was utilized. Pan-cancer correlations were calculated for each TILs and SUV39H2 gene expression and methylation and presented in the form of a heatmap. Scatterplots of SUV39H2 expression/methylation, as well as the correlation between individual TIL, were shown for statistically significant results. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered as statistically significant.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.7. Gene correlation analysis:\u003c/h2\u003e\u003cp\u003eTo explore the correlation between lamin genes (LMNB1, LMNB2, and LMNA) and SUV39H1/H2 in pan-cancer and ovarian cancer, the GEPIA2 webtool [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://gepia2.cancer-pku.cn\u003c/span\u003e\u003cspan address=\"http://gepia2.cancer-pku.cn\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (Tang et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Li et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)] was utilized. GEPIA2 is a valuable resource that leverages data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project. Spearman Correlation between gene expression was computed and scatter plots were generated to visualize expression relationships. Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Pan-Cancer correlations were performed using aggregated TCGA RNA-seq data comprising 33 cancer types. Pan-cancer heatmap of Spearman correlation between SUV39H1 and SUV39H2 and lamin genes were calculated using TIMER2.0 webtool [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://compbio.cn/timer2/\u003c/span\u003e\u003cspan address=\"https://compbio.cn/timer2/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e] (Li et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e2.8. Statistical Analysis for experimental data:\u003c/h2\u003e\u003cp\u003eThe drug treatment experiments were repeated 3 times, and densitometric quantification of western blot images was performed using ImageJ software. Statistical analysis of variance (ANOVA) was performed, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (N\u0026thinsp;=\u0026thinsp;3 replicates) was considered statistically significant. For Immunofluorescence imaging, images were processed with ImageJ software, and fluorescence intensities were calculated and plotted using GraphPad PRISM software. Statistical analysis was performed using the Mann-Whitney t- test, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Pan-cancer expression profile of SUV39H1 and SUV39H2\u003c/h2\u003e\u003cp\u003eTo elucidate the transcriptional landscape of the SUV39 family of histone methyltransferases, we systematically analyzed the expression of SUV39H1 and SUV39H2 across 33 tumor types from The Cancer Genome Atlas (TCGA) dataset. Expression levels (log₂ TPM) were compared between tumor and normal samples, and distinct overexpression patterns were observed for both members across multiple types of cancer.\u003c/p\u003e\u003cp\u003eSUV39H1 displayed a widespread and significant upregulation across numerous malignancies, including breast invasive carcinoma (BRCA), cholangiocarcinoma (CHOL), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The degree of overexpression was particularly striking in KIRC, GBM, and CHOL, where SUV39H1 levels were several-fold higher than in adjacent normal tissues (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn parallel, SUV39H2 exhibited a similar but more tumor-restricted expression pattern, being significantly upregulated in BRCA, CHOL, ESCA, GBM, head and neck squamous cell carcinoma (HNSC), KIRC, LIHC, LUAD, and STAD (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Notably, SUV39H2 expression was markedly elevated in testicular germ cell tumors (TGCT) and renal carcinomas, consistent with its known germline-associated and proliferative expression characteristics.\u003c/p\u003e\u003cp\u003eImportantly, metastatic tumor samples, wherever available (such as in SKCM, UVM, and BRCA datasets), also demonstrated high expression levels of SUV39H1 and SUV39H2, suggesting their potential involvement in metastatic progression and the maintenance of chromatin reprogramming in advanced disease states (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, b).\u003c/p\u003e\u003cp\u003eWithin the HNSC cohort, where HPV status was annotated, a distinct expression difference was observed: HPV-negative tumors exhibited significantly higher SUV39H1 and SUV39H2 expression compared to HPV-positive counterparts. These findings suggest that upregulation of SUV family methyltransferases may be preferentially associated with HPV-independent oncogenic pathways and potentially linked to chromatin-driven tumorigenic mechanisms in HNSC.\u003c/p\u003e\u003cp\u003eThe summary visualization (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec) provides an integrated overview of log₂ fold-change (log₂FC) values and adjusted significance (\u0026ndash;log₁₀ p-adj) across tumor types for both enzymes. Overall, SUV39H1 demonstrated a more consistently high and significant upregulation across a greater number of cancer types than SUV39H2, indicating that SUV39H1 is the more ubiquitously dysregulated member of the family. In contrast, SUV39H2 exhibited stronger but more selective upregulation, particularly in germ cell, renal, and liver cancers, suggesting tissue- or lineage-specific transcriptional control. The red intensity of the log₂FC in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec highlights this distinction, where SUV39H1 is broadly elevated across epithelial and solid tumors, and SUV39H2 reaches its highest expression amplitude in select tumor types such as TGCT, KIRC, and LIHC.\u003c/p\u003e\u003cp\u003eCollectively, these data establish that SUV39H1 and SUV39H2 are broadly overexpressed in human cancers, with SUV39H1 showing widespread and consistent dysregulation, while SUV39H2 displays strong but cancer-type\u0026ndash;restricted activation. Their elevated expression in both primary and metastatic tumors, coupled with differences by HPV status, highlights their potential contribution to epigenetic reprogramming, chromatin condensation, and nuclear architectural alterations that support malignant progression. Taken together, these findings reveal distinct yet overlapping expression profiles of SUV39H1 and SUV39H2 across human cancers, emphasizing their potential oncogenic relevance and chromatin regulatory functions. To further explore the clinical implications of this dysregulation, we next assessed the prognostic significance of SUV39H1 and SUV39H2 expression across TCGA cancer types.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Prognostic significance of SUV39H1 and SUV39H2 expression across cancers\u003c/h2\u003e\u003cp\u003eTo determine the clinical relevance of SUV39H1 and SUV39H2 upregulation, we next evaluated their association with overall survival (OS) and disease-free survival (DFS) across TCGA cancer cohorts.\u003c/p\u003e\u003cp\u003eAt the pan-cancer level, patients with high SUV39H1 and SUV39H2 expression showed a significant reduction in both OS and DFS compared to those with low expression (log-rank p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). This trend indicates that elevated expression of either methyltransferase is broadly associated with poor patient prognosis across multiple tumor types.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo systematically identify cancer-specific prognostic associations, we performed univariate Cox regression analysis across 33 cancers (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). The resulting heatmaps revealed that SUV39H1 overexpression was significantly associated with worse OS and DFS in cancers such as adrenocortical carcinoma (ACC), glioblastoma multiforme (GBM), sarcoma (SARC), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), and lung adenocarcinoma (LUAD) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). SUV39H2, while showing fewer associations overall, displayed notable negative prognostic impact in GBM, testicular germ cell tumor (TGCT), SARC, and ACC, highlighting its importance in specific tumor contexts (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e\u003cp\u003eKaplan\u0026ndash;Meier analyses across individual cancer types further confirmed these associations. For disease-free survival, high SUV39H1 expression predicted significantly shorter survival in ACC, KIRC, prostate adenocarcinoma (PRAD), and uterine corpus endometrial carcinoma (UCS) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). Similarly, SUV39H2 high-expression cohorts exhibited poorer DFS outcomes in ACC, GBM, SARC, and TGCT (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed), supporting its role in tumor relapse and progression.\u003c/p\u003e\u003cp\u003eFor overall survival, consistent trends were observed. Patients with high SUV39H1 expression had markedly reduced OS in ACC, cervical squamous cell carcinoma (CESC), skin cutaneous melanoma (SKCM), and uveal melanoma (UVM) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee). Elevated SUV39H2 expression was also associated with poor OS in ACC, breast invasive carcinoma (BRCA), kidney chromophobe (KICH), LIHC, LUAD, mesothelioma (MESO), SARC, and thyroid carcinoma (THCA) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ef). Notably, among all tumor types, ACC, GBM, and SARC emerged as high-risk cancers where elevated expression of both SUV39H1 and SUV39H2 correlated with significantly shorter OS and DFS, suggesting cooperative or compensatory functions of these methyltransferases in promoting aggressive tumor phenotypes.\u003c/p\u003e\u003cp\u003eTogether, these findings demonstrate that SUV39H1 and SUV39H2 overexpression correlates with poor clinical outcomes across multiple cancers, with SUV39H1 exerting a more widespread prognostic impact, while SUV39H2 displays cancer-type\u0026ndash;restricted but potent effects. These results identify the SUV39 family as independent prognostic indicators and potential epigenetic drivers of tumor progression in diverse malignancies.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.3. SUV39H1 and SUV39H2 are upregulated in ovarian cancer and predict poor survival\u003c/h2\u003e\u003cp\u003eGiven the consistent pan-cancer association of SUV39H1 and SUV39H2 with adverse prognosis, we next focused our analysis on ovarian cancer, one of the most lethal gynecological malignancies. Ovarian cancer remains the third leading cause of cancer-related death among women in India (Bray et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), largely due to late-stage diagnosis, extensive peritoneal metastasis, and the high rate of recurrence following chemotherapy. Among its subtypes, high-grade serous ovarian carcinoma (HGSOC) accounts for nearly 70\u0026ndash;80% of all cases and is characterized by extensive genomic instability, frequent TP53 mutations, and widespread epigenetic dysregulation.\u003c/p\u003e\u003cp\u003eGiven the critical role of chromatin-modifying enzymes in regulating genome stability and gene expression, we hypothesized that aberrant activity of SUV39 family histone methyltransferases could contribute to the aggressive phenotype of ovarian tumors. Furthermore, gynecological malignancies often exhibit alterations in chromatin states and lamina-associated heterochromatin, making this cancer type particularly relevant to investigate the nuclear architectural functions of SUV-family enzymes.\u003c/p\u003e\u003cp\u003eTo explore this, we first analyzed the expression levels of SUV39H1 and SUV39H2 in ovarian cancer tissues compared to normal ovarian samples using the TCGA and GEO (GSE27651) datasets. In the TCGA ovarian cancer cohort, both SUV39H1 and SUV39H2 were significantly upregulated in ovarian tumor tissues compared with normal controls (p\u0026thinsp;=\u0026thinsp;2.85\u0026times;10⁻\u0026sup3;⁸ and p\u0026thinsp;=\u0026thinsp;1.48\u0026times;10⁻⁵⁰, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). Consistent with this, in the GSE27651 dataset, which includes normal ovarian surface epithelium (OSE, n\u0026thinsp;=\u0026thinsp;6) and high-grade serous ovarian carcinoma (HGSOC, n\u0026thinsp;=\u0026thinsp;22), both SUV39H1 and SUV39H2 mRNA levels were markedly elevated in HGSOC samples (****p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed). These findings confirm that SUV39-family members are consistently overexpressed in ovarian cancer across independent datasets, suggesting a conserved epigenetic alteration in this malignancy.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNext, to evaluate their prognostic relevance, Kaplan\u0026ndash;Meier survival analyses were performed. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee, high SUV39H2 expression was significantly associated with poorer overall survival (hazard ratio [HR]\u0026thinsp;=\u0026thinsp;3.27, 95% CI\u0026thinsp;=\u0026thinsp;1.33\u0026ndash;8.03; log-rank p\u0026thinsp;=\u0026thinsp;0.0066), with a median survival of 30 months compared to 143 months for the low-expression group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee).\u003c/p\u003e\u003cp\u003eWhile SUV39H1 also showed a trend toward reduced survival in the high-expression cohort (HR\u0026thinsp;=\u0026thinsp;2.36; p\u0026thinsp;=\u0026thinsp;0.11), this did not reach statistical significance (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ef), possibly due to the smaller cohort size or differential functional contribution between the two paralogs. Collectively, these results demonstrate that both SUV39H1 and SUV39H2 are transcriptionally upregulated in ovarian cancer, and that SUV39H2 expression, in particular, serves as a strong indicator of poor patient prognosis. These data highlight the SUV39 family as potential epigenetic drivers of ovarian tumorigenesis, justifying further exploration of their functional and mechanistic roles in this malignancy.\u003c/p\u003e\u003cp\u003eWestern blot analysis was performed to assess the expression levels of SUV39H2 protein across multiple ovarian cancer cell lines, including A2780, IGROV1, OVCAR3, OVCAR4, OVCAR5, and OVCAR8. Specific probing for SUV39H2 revealed that the A2780 cell line exhibited the strongest and most intense band corresponding to SUV39H2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eg), indicating significantly higher protein levels compared to the other cell lines. In contrast, SUV39H1 expression was higher in IGROV1 and OVCAR4 cell lines, whereas OVCAR3 and OVCAR5 showed very faint SUV39H1 bands, indicating minimal expression (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eg). Beta-actin, used as a loading control, was consistently expressed across all samples. These results identify A2780 as the optimal model for studying SUV39H2-related functions in ovarian cancer, as it exhibits the highest expression in this cell line.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.4. SUV39H2-Associated Tumor-Infiltrating Lymphocyte (TIL) Infiltration in Ovarian Cancer\u003c/h2\u003e\u003cp\u003eGiven the strong association between SUV39H2 overexpression and poor patient prognosis in ovarian cancer, we next sought to explore the potential mechanisms underlying this adverse clinical outcome. Tumor progression and therapy resistance in ovarian cancer are profoundly influenced by the tumor immune microenvironment (TIME), where altered chromatin landscapes can reprogram immune-related gene expression and modulate immune cell infiltration. As an epigenetic regulator, SUV39H2-mediated H3K9 trimethylation (H3K9me3) is known to promote the transcriptional silencing of genes involved in immune and inflammatory responses, thereby facilitating immune escape and tumor tolerance.\u003c/p\u003e\u003cp\u003eTo determine whether SUV39H2 expression correlates with changes in immune infiltration, we performed a comprehensive analysis using the TISIDB platform, integrating tumor-infiltrating lymphocyte (TIL) profiles with gene expression data. This analysis enabled us to assess whether the epigenetic activation of SUV39H2 contributes to an immunosuppressive phenotype in ovarian cancer. The results, detailed in the following section, reveal that high SUV39H2 expression is associated with a marked reduction in multiple T-cell, B-cell, NK-cell, and myeloid cell subsets, suggesting that SUV39H2 may actively shape an immune-excluded tumor microenvironment.\u003c/p\u003e\u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\u003ch2\u003e3.4.1. SUV39H2 Expression and Immune Cell Infiltration\u003c/h2\u003e\u003cp\u003eAnalysis using TISIDB was performed to investigate the relationship between SUV39H2 gene expression and tumor-infiltrating lymphocyte (TIL) abundance in ovarian cancer (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Scatter plot data revealed a predominantly negative correlation between SUV39H2 expression and the infiltration levels of most immune cell types within the tumor microenvironment (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Specifically, elevated SUV39H2 expression was associated with a marked decrease in key immune populations, including central memory and effector memory CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e T cells, T helper subsets (Th1, Th17), follicular helper T cells (Tfh), regulatory T cells (Tregs), as well as immature and activated B cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Natural killer (NK) cells and several myeloid cells\u0026mdash;including neutrophils, eosinophils, monocytes, and macrophages\u0026mdash;also showed reduced infiltration concurrent with higher SUV39H2 levels. Among these, effector memory CD8\u0026thinsp;+\u0026thinsp;T cells and eosinophils exhibited the strongest negative associations. Notably, two immune cell types\u0026mdash;activated CD4\u003csup\u003e+\u003c/sup\u003e T cells and T helper 2 (Th2) cells\u0026mdash;demonstrated a positive correlation with SUV39H2 expression, suggesting selective immune modulation by this gene (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThese findings imply that increased SUV39H2 expression may contribute to an immunosuppressive tumor microenvironment by broadly reducing the infiltration of multiple immune cell subsets, potentially facilitating tumor immune evasion in ovarian cancer.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section3\"\u003e\u003ch2\u003e3.4.2. SUV39H2 Methylation and Immune Cell Abundance\u003c/h2\u003e\u003cp\u003eFurther analysis assessed correlations between SUV39H2 gene methylation status and TIL abundance in ovarian tumors. Methylation, which generally represses gene activity, showed weak positive trends with increased infiltration of γδ T cells (Tgd) and Th2 cells, although these associations lacked strong statistical support. Conversely, a more robust negative correlation was identified between SUV39H2 methylation and neutrophil infiltration (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), indicating that higher methylation levels are linked with reduced neutrophil presence. Additional weaker negative trends were observed for effector and central memory CD8\u003csup\u003e+\u003c/sup\u003e T cells, immature B cells, plasmacytoid dendritic cells (pDCs), immature dendritic cells (iDCs), and activated CD8\u003csup\u003e+\u003c/sup\u003e and CD4\u003csup\u003e+\u003c/sup\u003e T cells, as well as activated B cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIt is essential to note that these methylation-related observations are preliminary and derived from a limited dataset of nine ovarian cancer cases, which limits their generalizability. These correlations should be interpreted cautiously, as they do not establish causality and may be influenced by other biological factors. Nonetheless, the data provide initial evidence that SUV39H2 methylation might modulate the immune landscape in ovarian tumors, with potential implications for tumor immune evasion mechanisms. Future larger-scale studies are necessary to validate and clarify the functional impact of SUV39H2 methylation on immune infiltration in ovarian cancer.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e3.5. SUV39H1/2 Correlates with B-Type Lamins Across Ovarian and Pan-Cancer Cohorts\u003c/h2\u003e\u003cp\u003eGiven the association of SUV39H2 overexpression with an immunosuppressive tumor microenvironment in ovarian cancer, we next examined whether these methyltransferases also influence nuclear structural components that are central to genome organization and chromatin stability. Since lamins, particularly Lamin B1 (LMNB1) and Lamin B2 (LMNB2), are key determinants of nuclear architecture and heterochromatin anchoring at the nuclear periphery and were also largely upregulated in multiple cancers (Kundu et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), we investigated potential transcriptional correlations between SUV39 family enzymes and lamin genes across ovarian cancer and a Pan-Cancer cohort.\u003c/p\u003e\u003cp\u003eCorrelation analyses revealed moderate to strong positive associations between SUV39H1 and SUV39H2, and B-type lamins (LMNB1 and LMNB2), suggesting a coordinated regulatory relationship (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ea, b). In ovarian cancer, SUV39H2 expression correlated with LMNB1 (R\u0026thinsp;=\u0026thinsp;0.49) and LMNB2 (R\u0026thinsp;=\u0026thinsp;0.42), while SUV39H1 displayed similar correlations (R\u0026thinsp;=\u0026thinsp;0.40 and R\u0026thinsp;=\u0026thinsp;0.39, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ee, f). These associations were further strengthened in the Pan-Cancer dataset, where SUV39H2 correlated with LMNB1 (R\u0026thinsp;=\u0026thinsp;0.56) and LMNB2 (R\u0026thinsp;=\u0026thinsp;0.47), and SUV39H1 with LMNB1 (R\u0026thinsp;=\u0026thinsp;0.56) and LMNB2 (R\u0026thinsp;=\u0026thinsp;0.52) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ec, d). These consistent patterns across multiple cancer types suggest a conserved functional linkage between SUV39 enzymes and B-type lamins in maintaining nuclear organization during tumorigenesis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn contrast, LMNA, which encodes Lamin A/C, showed weak or negligible correlations with both methyltransferases. In ovarian cancer, SUV39H2 and LMNA exhibited a slight negative correlation (R = \u0026minus;\u0026thinsp;0.098) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ee), while correlations in the Pan-Cancer cohort were minimal (SUV39H2: R = \u0026minus;\u0026thinsp;0.02; SUV39H1: R\u0026thinsp;=\u0026thinsp;0.15) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ec, d). Importantly, Lamin A expression is typically downregulated in several cancer types, including breast, colorectal, and ovarian malignancies, where its reduced levels are linked to increased nuclear deformability, metastatic dissemination, and poor prognosis. Conversely, higher Lamin A expression has been associated with improved patient survival and more differentiated tumor phenotypes, underscoring its potential as a tumor suppressor.\u003c/p\u003e\u003cp\u003eGiven that SUV39H1 and SUV39H2 catalyze H3K9 trimethylation (H3K9me3) to promote heterochromatin formation and gene silencing, the observed inverse trend between SUV39 expression and Lamin A suggests that Lamin A may be a downstream target of SUV39H1/H2-mediated epigenetic repression. Such regulation could facilitate chromatin compaction and nuclear architectural remodeling, enabling tumor cells to adopt more plastic and aggressive phenotypes.\u003c/p\u003e\u003cp\u003eFunctionally, the positive association of SUV39H1/2 with B-type lamins implies a cooperative role in preserving repressive nuclear organization. In contrast, the negative association with Lamin A/C highlights a potential mechanism by which SUV39 overexpression contributes to the loss of nuclear rigidity and increased tumor adaptability. In summary, these results reveal a robust co-expression relationship between SUV39H1/2 and B-type lamins (LMNB1, LMNB2) across ovarian and other cancers, suggesting a coordinated role in maintaining nuclear structural integrity and heterochromatin repression. Conversely, the suppression of Lamin A/C expression by SUV39H1/2 may represent an adaptive mechanism that enhances malignant progression by promoting nuclear deformability and epigenetic plasticity.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003e3.6. Chaetocin-Mediated Inhibition of SUV39H2 Upregulates Lamin A in Ovarian Cancer Cells\u003c/h2\u003e\u003cp\u003eBuilding upon the observed negative correlation between SUV39H family members and A-type lamins, we next sought to validate whether SUV39H2 activity directly influences nuclear lamina components experimentally. To this end, ovarian cancer A2780 cells were treated with chaetocin, a fungal metabolite and an inhibitor of SUV39H1/2, at concentrations of 300 nM and 600 nM, followed by assessment of Lamin A and Lamin C expression.\u003c/p\u003e\u003cp\u003eWestern blot analysis revealed a dose-dependent upregulation of Lamin A/C following pharmacological inhibition of SUV39H2 using chaetocin in A2780 ovarian cancer cells. Lamin A expression remained largely unchanged at 300 nM chaetocin, whereas a statistically significant increase was observed at 600 nM, indicating that suppression of SUV39H2 enzymatic activity enhances Lamin A expression (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003ea, b). Similarly, Lamin C exhibited a comparable expression pattern, with a modest elevation at 300 nM and a marked induction at 600 nM chaetocin, suggesting that SUV39H2 inhibition derepresses Lamin A/C expression (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003ea, b). These findings support a potential epigenetic regulatory link between SUV39H2 activity and Lamin A/C expression, wherein SUV39H2 may act as a negative modulator of LMNA transcription or stability, thereby influencing nuclear structure and cancer cell phenotype.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eImmunofluorescence microscopy further corroborated these findings. Untreated A2780 cells exhibited the characteristic ring-like peripheral localization of Lamin A, consistent with its nuclear envelope distribution. Following 600 nM Chaetocin treatment, the intensity of Lamin A staining was visibly enhanced, with quantitative analysis confirming a significant increase (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) in fluorescence intensity relative to the controls (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003ec, d). Notably, the nuclear localization pattern remained intact, indicating that the observed increase reflects elevated protein expression rather than mislocalization or structural disruption. Line-scan analysis further confirmed these findings and also revealed differences in the intensity of lamin A across the nuclear periphery, suggesting an observed increase in lamin A protein expression in SUV39h1/h2-inhibited cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003ed).\u003c/p\u003e\u003cp\u003eCollectively, these results demonstrate that inhibition of SUV39H2 leads to upregulation of Lamin A in ovarian cancer cells, suggesting a regulatory axis between SUV39H2-mediated histone methylation and nuclear lamina integrity. The dose-dependent and isoform-specific effects observed for Lamin A and Lamin C highlight the complex interplay between epigenetic enzymes and structural nuclear proteins, providing mechanistic insight into how SUV39H2 may contribute to nuclear architecture remodeling and tumor progression.\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eSUV39H1 and SUV39H2, the two canonical H3K9 trimethyltransferases, are central to the establishment and maintenance of transcriptionally repressive heterochromatin (Peters et al.,2001). By catalyzing the trimethylation of histone H3 lysine 9 (H3K9me3), these enzymes enforce epigenetic silencing of gene expression, preserve genomic integrity, and sustain higher-order chromatin organization (Rea et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2000\u003c/span\u003e). Although their roles in heterochromatin formation and genome stability are well established, their cancer-specific functions and interplay with structural nuclear components remain insufficiently understood. Recent evidence has begun to reveal that these methyltransferases not only regulate gene expression but also influence tumor cell plasticity, immune evasion, and nuclear morphology, which are hallmarks that define malignant progression (Li et al.,2025).\u003c/p\u003e\u003cp\u003eIn this study, we provide a comprehensive multidimensional analysis of SUV39H1 and SUV39H2 across human cancers, integrating transcriptomic, prognostic, immune infiltration, methylation, and structural correlation data. Our findings reveal distinct yet overlapping oncogenic landscapes for these enzymes, positioning them as key epigenetic regulators at the interface between chromatin state, immune modulation, and nuclear architecture.\u003c/p\u003e\u003cp\u003eOur comprehensive analysis reveals that SUV39H2 is broadly overexpressed across multiple human cancers, including acute myeloid leukemia (AML), breast, colon, esophageal, lung, ovarian, prostate, stomach, and endometrial cancers. Particularly striking is its marked upregulation in AML and testicular tumors, where the difference between normal and tumor tissues underscores its potential as a diagnostic biomarker. The restricted expression of SUV39H2 in normal tissues, in contrast to its pronounced elevation in tumor contexts, underscores its therapeutic promise as a tumor-selective target. Given its role in epigenetic repression, it is plausible that SUV39H2 drives oncogenesis through silencing of tumor suppressor genes, promoting dedifferentiation, and sustaining cellular plasticity. Similarly, SUV39H1 exhibits significant upregulation in several cancer types, including AML, breast, colon, liver, lung, and testicular cancers. In AML, its strong expression suggests a function in preserving the undifferentiated state of leukemic blasts through persistent repressive chromatin programming (Chakraborty et al.,2003). In contrast, its moderate upregulation in prostate, esophageal, pancreatic, and rectal cancers suggests a supportive or secondary role in tumor progression. Notably, SUV39H1 expression remains low in renal and thyroid cancers, highlighting the context-dependent nature of its oncogenic potential and suggesting the existence of lineage-specific epigenetic dependencies.\u003c/p\u003e\u003cp\u003eA key finding of this study is the robust prognostic relevance of SUV39H1 and SUV39H2 in high-grade serous ovarian cancer (HGSOC). Both genes are significantly overexpressed in tumor tissues relative to normal ovarian surface epithelium, but SUV39H2 stands out as a particularly strong predictor of poor patient outcomes. High SUV39H2 expression correlates with a median overall survival of 30 months compared to 143 months in the low-expression cohort, with a hazard ratio of 3.27, establishing it as a potent negative prognostic biomarker. Although SUV39H1 shows a similar pattern, its prognostic strength is comparatively lower. These data implicate SUV39H2 as a key driver of aggressive disease behavior in HGSOC, potentially by enforcing epigenetic silencing of immune-modulatory or differentiation-related genes, thereby fostering immune evasion and maintaining malignant plasticity (Saha and Muntean \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eImmune infiltration analyses further support the immunosuppressive role of SUV39H2. Its high expression negatively correlates with the abundance of multiple immune effector subsets, including effector memory CD8⁺ T cells, regulatory T cells, B cells, NK cells, and myeloid-derived cells. This immune-exclusion phenotype suggests that SUV39H2 may actively remodel the chromatin landscape of immune-regulatory genes to dampen anti-tumor immune responses. Interestingly, a positive association with Th2 and activated CD4⁺ T cells was observed, indicative of a shift toward an immunosuppressive tumor microenvironment. Furthermore, the inverse relationship between SUV39H2 promoter methylation and immune infiltration, particularly involving neutrophils and plasmacytoid dendritic cells, implies that DNA methylation\u0026ndash;dependent regulation of SUV39H2 may fine-tune its immunomodulatory impact, potentially establishing a feedback circuit that reinforces immune escape.\u003c/p\u003e\u003cp\u003eAnother important insight from this study is the discovery of a positive correlation between SUV39H1/H2 expression and nuclear lamina components specifically B-type lamins i.e. LMNB1 and LMNB2. Lamin B proteins are structural determinants of nuclear integrity and play crucial roles in heterochromatin tethering and spatial genome organization (Dechat et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2008\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; van Steensel and Belmont \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Sobo et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). We have previously shown that B-type lamin expression in strongly associated with cancer progression (Kundu et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). The co-expression pattern btween B-type lamins and SUV39H1/H2 enzymes observed in this study suggests that SUV39 enzymes may cooperate with Lamin B to maintain nuclear architecture and chromatin compartmentalization in cancer cells. This relationship may reflect a functional axis wherein SUV39-mediated H3K9me3 deposition stabilizes peripheral heterochromatin domains in coordination with Lamin B, thereby promoting a transcriptionally repressive nuclear environment that favors tumor cell survival and adaptation (Harr et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). In contrast, Lamin A (LMNA) exhibits an inverse relationship with SUV39H1 and SUV39H2, suggesting a differential regulatory paradigm. LMNA is often downregulated in cancers (Chiarini et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022a\u003c/span\u003e; Kundu et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), and its loss has been associated with increased nuclear deformability, enhanced proliferation, and metastatic dissemination (Bell et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). The observed negative correlation thus suggests that SUV39 enzymes might epigenetically repress LMNA expression, contributing to structural and mechanical alterations that facilitate tumor aggressiveness.\u003c/p\u003e\u003cp\u003eExperimental validation using the SUV39H2 inhibitor chaetocin further substantiates this hypothesis. Treatment of A2780 ovarian cancer cells with chaetocin resulted in a clear restoration of Lamin A protein levels, particularly those localized at the nuclear envelope, as confirmed by both immunofluorescence and Western blot analysis. This restoration suggests that SUV39H2 represses LMNA transcription through H3K9me3-mediated silencing and that its inhibition can reverse this repression. Considering the established tumor-suppressive roles of Lamin A, the reactivation of LMNA upon SUV39H2 inhibition suggests a potential therapeutic strategy in which targeting SUV39H2 could restore nuclear architecture integrity and re-establish anti-oncogenic mechanical constraints. Given that Lamin A deficiency contributes to enhanced cellular plasticity and invasiveness, SUV39H2 inhibition may not only attenuate tumor growth but also limit metastatic potential by reprogramming nuclear organization (Chiarini et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2022b\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn summary, this study elucidates the multifaceted role of SUV39H1 and SUV39H2 in cancer progression, extending beyond canonical chromatin repression to encompass immune modulation and nuclear structural regulation. SUV39H2, in particular, emerges as a key oncogenic epigenetic effector and prognostic marker, especially in ovarian cancer. Its strong association with immune exclusion and Lamin B enrichment, coupled with suppression of Lamin A, highlights its dual role in reconfiguring both the transcriptional and structural landscapes of cancer cells. These findings position SUV39H2 not only as a biomarker of poor prognosis but also as a promising therapeutic target for re-establishing tumor-suppressive chromatin and nuclear architecture. Further mechanistic and translational studies are warranted to elucidate how SUV39H2 integrates with Lamin-mediated nuclear scaffolding and immune evasion pathways, thereby opening new avenues for precision epigenetic therapy in malignancies characterized by SUV39H2 overexpression.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eDeclaration of Interest\u003c/h2\u003e\n\u003cp\u003eThe authors report no financial or non-financial conflicts of interest.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThe work was supported by grants from the Science and Engineering Research Board, Department of Science and Technology (DST-SERB), Government of India, with grant number ECR/2016/001740 and AIIMS intramural funding. SK, thanks to the University Grants Commission, India, for fellowship support.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eSK was involved in conceptualisation, visualization, methodology, data analysis, data interpretation, manuscript writing, editing, and reviewing; AR was involved in manuscript writing, reviewing, and editing, conducting experiments; AK and AS were involved in manuscript writing, reviewing, editing, supervision, and funding acquisition.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eThe authors thank Prof. Adam R Karpf, Nebraska Medical Center, Omaha, USA, for providing ovarian cancer cell lines as a generous gift. The authors thank the All India Institute of Medical Sciences, New Delhi, India, for providing all necessary support. The authors thank the Confocal Microscopy Facility, Centralized Core Research Facility, AIIMS, New Delhi, for their assistance with confocal image acquisition and analysis.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets analyzed in the current study are publicly available in The Cancer Genome Atlas ( [https://www.cancer.gov/tcga](https:/www.cancer.gov/tcga) ) database, Gene Expression Omnibus (GEO) database ( [https://www.ncbi.nlm.nih.gov/geo/](https:/www.ncbi.nlm.nih.gov/geo) ) under accession number GSE27651, TIMER2.0 ( [https://compbio.cn/timer2/](https:/compbio.cn/timer2) ), GEPIA2 ( [http://gepia2.cancer-pku.cn/](http:/gepia2.cancer-pku.cn) ), TISIDB ( [https://cis.hku.hk/TISIDB/index.php](https:/cis.hku.hk/TISIDB/index.php) ), and TNMplot ( [https://tnmplot.com/analysis/](https:/tnmplot.com/analysis) ) database.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAllis, C. 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Oncol.\u003c/em\u003e \u003cb\u003e25\u003c/b\u003e, 2438\u0026ndash;2450. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/S12094-023-03128-2/METRICS\u003c/span\u003e\u003cspan address=\"10.1007/S12094-023-03128-2/METRICS\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023b).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"SUV39H2, H3K9me3, ovarian cancer, Lamin B, epigenetic repression, immune evasion","lastPublishedDoi":"10.21203/rs.3.rs-8137620/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8137620/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEpigenetic regulation of chromatin structure is a key determinant of transcriptional control and nuclear organization in cancer. Among histone lysine methyltransferases, SUV39H1 and SUV39H2 catalyze the trimethylation of histone H3 lysine 9 (H3K9me3), establishing repressive heterochromatin domains that are essential for genomic stability. However, their pan-cancer expression dynamics, prognostic value, and structural implications remain poorly defined. In this study, we performed an integrative analysis of SUV39H1 and SUV39H2 across the Cancer Genome Atlas (TCGA) cohort to investigate their expression, prognostic relevance, associations with the immune landscape, and interactions with nuclear lamina genes. Both enzymes were significantly overexpressed in multiple tumor types, with SUV39H2 showing particularly high expression in high-grade serous ovarian cancer (HGSOC), where elevated levels correlated with poor overall survival (HR\u0026thinsp;=\u0026thinsp;3.27, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Immune infiltration analysis revealed that high SUV39H2 expression was inversely associated with tumor-infiltrating lymphocytes, indicating an immunosuppressive tumor microenvironment. Correlation studies demonstrated strong positive associations between SUV39H1/H2 and Lamin B genes (LMNB1, LMNB2), implicating their role in maintaining nuclear architecture and heterochromatin tethering. Conversely, Lamin A (LMNA) exhibited weak or negative correlation with SUV39 enzymes. Functional validation in A2780 ovarian cancer cells demonstrated that pharmacological inhibition of SUV39H2 by Chaetocin resulted in the upregulation of Lamin A, indicating epigenetic repression of LMNA by SUV39H2. Collectively, our findings uncover a novel link between SUV39H2, chromatin\u0026ndash;lamina interactions, and immune evasion in ovarian cancer, providing a rationale for targeting SUV39H2 in therapeutic epigenetic interventions.\u003c/p\u003e","manuscriptTitle":"SUV Family Histone Methyltransferases Modulate Nuclear Lamin A and Drive Tumorigenesis: Integrative Pan-Cancer TCGA analysis and Experimental Evidence","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-10 19:04:34","doi":"10.21203/rs.3.rs-8137620/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-31T03:34:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-19T16:02:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-18T15:11:11+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-18T10:27:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"69226110163159288973310622536857756144","date":"2025-12-10T14:28:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284666973275749387837093536353712141324","date":"2025-12-10T10:19:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"192925676022958132581105202924505228126","date":"2025-12-10T09:03:47+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-08T06:29:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-08T05:54:58+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-01T13:23:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-29T00:16:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-11-29T00:09:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f9a630b1-fc44-4b06-87c5-bd8a8c328c3b","owner":[],"postedDate":"December 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":59357018,"name":"Biological sciences/Cancer"},{"id":59357019,"name":"Biological sciences/Computational biology and bioinformatics"},{"id":59357020,"name":"Biological sciences/Genetics"},{"id":59357021,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-04-13T16:01:37+00:00","versionOfRecord":{"articleIdentity":"rs-8137620","link":"https://doi.org/10.1038/s41598-026-44020-7","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-04-09 15:58:33","publishedOnDateReadable":"April 9th, 2026"},"versionCreatedAt":"2025-12-10 19:04:34","video":"","vorDoi":"10.1038/s41598-026-44020-7","vorDoiUrl":"https://doi.org/10.1038/s41598-026-44020-7","workflowStages":[]},"version":"v1","identity":"rs-8137620","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8137620","identity":"rs-8137620","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}