LSD1 promotes prostate cancer cell proliferation by upregulating PRAC1 expression

LSD1 promotes prostate cancer cell proliferation by upregulating PRAC1 expression | 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 LSD1 promotes prostate cancer cell proliferation by upregulating PRAC1 expression Yang Liao, Chuan Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7401472/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Mar, 2026 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract PRAC1 , which is specifically expressed in prostate, rectal, and distal colon tissues, plays a critical role in the maintenance and self-renewal of prostate epithelial stem cells. However, the role of PRAC1 in prostate cancer is unclear. In this study, we found that PRAC1 expression is upregulated in prostate cancer cells and that PRAC1 knockdown represses the proliferation of prostate cancer cells. Moreover, lysine-specific demethylase 1 (LSD1) promoted prostate cancer cell proliferation by upregulating PRAC1 expression. TAK-418, an LSD1 inhibitor, suppressed prostate cancer cell proliferation by downregulating PRAC1 expression. The results of this study highlight PRAC1 or LSD1 inhibition as promising avenues for prostate cancer treatment. Biological sciences/Cancer Biological sciences/Cell biology Health sciences/Oncology Health sciences/Urology prostate cancer proliferation PRAC1 LSD1 TAK-418 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Prostate cancer is a leading malignancy in men worldwide that contributes substantially to global male mortality. Although its incidence rates vary considerably across regions, with a higher prevalence in developed countries, emerging evidence suggests rising trends in developing nations owing to aging populations and lifestyle changes [ 1 , 2 ] . Prostate cancer poses substantial health risks, particularly for men aged > 50 years, those with a family history of the disease, and individuals of African descent, who face disproportionately higher morbidity and mortality [ 1 , 2 ] . Although prostate cancer often progresses indolently, advanced stages can aggressively metastasize to bones and organs, causing debilitating complications [ 3 , 4 ] . Early detection via prostate-specific antigen screening can improve outcomes; however, current therapies are limited by issues of overtreatment and substantial impacts on quality of life, highlighting the need for more balanced clinical approaches [ 3 , 4 ] . Specifically, the development of innovative noninvasive biomarker detection techniques holds considerable promise for enhancing diagnostic precision, personalizing therapeutic interventions, and ultimately reducing both overtreatment and the burden of prostate cancer. PRAC encodes a 382 nucleotide RNA and a 6-kDa nuclear protein found in the prostate, rectum, and distal colon. The PRAC gene is located on chromosome 17 at position 17q21, approximately 4 kb downstream of the homeodomain of Hoxb-13 [ 5 ] . PRAC1 mRNA is a specific marker distinguishing semen from other bodily fluids [ 6 ] . RNA in situ hybridization with a PRAC1 mRNA probe can detect exfoliated prostate cancer cells in urine [ 7 , 8 ] . Research has shown that PRAC expression is lower in prostate cancer tissues than in benign prostatic hyperplasia tissues [ 9 ] and that PRAC1 plays an essential role in the maintenance and self-renewal of prostate epithelial stem cells [ 10 ] . However, the role of PRAC1 in prostate cancer remains unclear. Therefore, we investigated the role of PRAC1 in prostate cancer in this study. We found that PRAC1 expression is upregulated in prostate cancer tissues compared to that in non-cancerous prostate tissues, and PRAC1 knockdown inhibits prostate cancer cell proliferation. Moreover, we found that lysine-specific demethylase 1 (LSD1) promotes PRAC1 expression in prostate cancer cells and that LSD1 inhibition represses prostate cancer cell proliferation by downregulating PRAC1 expression. Our findings highlight PRAC1 as a novel therapeutic target for prostate cancer therapy. Results PRAC1 knockdown inhibits prostate cancer cell proliferation To investigate the role of PRAC1 in prostate cancer, we compared the expression levels of PRAC1 in prostate cancer and non-cancerous prostate tissues using The Cancer Genome Atlas and the Genotype-Tissue Expression Portal. PRAC1 expression was upregulated in cancerous tissues compared to that in non-cancerous tissues (Fig. 1 a). Next, to investigate the effect of PRAC1 on cell proliferation, we knocked down PRAC1 in LNCaP and DU145 cells using two specific siRNAs (Fig. 1 b–c and Supplementary Fig. 1a–b). The MTS assay revealed that PRAC1 knockdown reduced cell proliferation (Fig. 1 d and Supplementary Fig. 1c). LSD1 promotes PRAC1 expression in prostate cancer cells To investigate the mechanism underlying the upregulation of PRAC1 expression in prostate cancer cells, we searched the GPSAdb database to identify candidate genes that may regulate PRAC1 expression. As shown in Table 1 , the knockdown of IQGAP3 , HSF1 , HSF2 , PRRC2B , LSD1 , POU5F1 , ARPIN , RB1 , ZZZ3 , TP53 , EWSR1 , ALKBH5 , BUB3 , or RUVBL1 led to the downregulation of PRAC1 expression. Additionally, we found that the mRNA expression levels of PRAC1 were positively correlated with those of LSD1 in prostate cancer and non-cancerous prostate tissues (Fig. 2 a and Table 1 ) and that the mRNA expression levels of LSD1 were upregulated in prostate cancer tissues compared to those in non-cancerous prostate tissues (Fig. 2 b). These data suggest that LSD1 may promote PRAC1 expression in prostate cancer tissues. Table 1 Genes that can regulate PRAC1 expression pbgene Method Cell line logFC P value *R value IQGAP3 siRNA NTERA-2 cl.D1 -8.184598395 9.16E-12 0.03 HSF1 siRNA MCF 7.00 -5.067259342 3.41E-12 -0.2 HSF2 siRNA MCF 7.00 -4.474306955 2.60E-05 -0.28 PRRC2B shRNA HEK293T -3.979308572 3.44E-05 -0.15 LSD1 shRNA A-673 -3.801029854 2.44E-121 0.27 POU5F1 shRNA iPSCs -3.787135872 1.15E-05 -0.3 ARPIN shRNA LoVo -3.173206952 1.95E-08 0.089 RB1 shRNA PC-3 -3.043327119 1.58E-06 -0.14 ZZZ3 siRNA WA17 -2.609872037 2.89E-11 -0.04 TP53 shRNA LNCaP clone FGC -2.574998038 3.52E-142 0.083 RB1 shRNA LNCaP C4-2 -2.39566212 1.92E-97 -0.14 EWSR1 siRNA A-673 -2.138551717 4.62E-50 -0.24 ALKBH5 ko hESCs -2.126864494 5.03E-09 -0.16 BUB3 shRNA LNCaP -2.118112727 1.97E-30 0.06 EWSR1 siRNA A-673 -2.082121605 6.99E-05 -0.24 RUVBL1 shRNA BPH-1 -2.061111305 1.22E-19 0.089 * The expression correlation between PRAC1 and indicated genes in prostate cancer tissues and non-cancerous prostate tissues. To investigate the regulatory role of LSD1 in PRAC1 expression, we knocked down LSD1 in prostate cancer cells and found that LSD1 knockdown inhibited PRAC1 expression (Fig. 3 a–c and Supplementary Fig. 2a–c). Furthermore, treatment with TAK-418, a specific LSD1 inhibitor, suppressed PRAC1 expression in a dose-dependent manner (Fig. 3 d–e and Supplementary Fig. 2d–e). Taken together, these data indicate that LSD1 promotes PRAC1 expression in prostate cancer cells. TAK-418 represses prostate cancer cell proliferation by inhibiting PRAC1 expression Given that LSD1 promotes the expression of PRAC1 and inhibiting PRAC1 expression suppresses the proliferation of prostate cancer cells, we investigated whether LSD1 inhibition can repress prostate cancer cell proliferation by suppressing PRAC1 expression. The specific knockdown of LSD1 in prostate cancer cells significantly inhibited cellular proliferation (Fig. 4 a–d), whereas PRAC1 overexpression partially rescued this effect (Fig. 4 e–f). Moreover, treatment with TAK-418 repressed prostate cancer cell proliferation (Fig. 5 a–b), yet PRAC1 overexpression partially rescued this effect (Fig. 5 c–d). Discussion PRAC1 is specifically expressed in prostate, rectal, and distal colon tissues and plays a critical role in the maintenance and self-renewal of prostate epithelial stem cells. Notably, PRAC1 mRNA serves as a semen-specific biomarker for forensic identification, enabling the noninvasive detection of exfoliated prostate cancer cells in urine [ 5 – 8 ] . In this study, we found that PRAC1 expression is upregulated in prostate cancer cells, and that PRAC1 knockdown represses prostate cancer cell proliferation. These findings identify PRAC1 as a potential therapeutic target in prostate cancer. LSD1 is an evolutionarily conserved histone demethylase that dynamically regulates the chromatin structure and gene transcription by removing methyl groups from histone H3 lysine residues at positions 4 (H3K4) and 9 (H3K9) via oxidative reactions. As a core component of multiprotein complexes (e.g., CoREST/histone deacetylase complexes), LSD1 mediates transcriptional repression via H3K4 demethylation, and participates in stem cell differentiation, embryonic development, and hematopoietic cell maturation [ 9 , 11 – 14 ] . In nuclear receptor signaling pathways such as androgen receptor signaling, LSD1 removes repressive H3K9 methylation marks to activate target gene transcription and promote prostate cancer cell proliferation [ 15 , 16 ] . LSD1 also exhibits non-histone substrate specificity, regulating the methylation status of proteins such as p53 and DNMT1 to influence the DNA damage response and DNA methylation homeostasis [ 15 , 17 , 18 ] . The activity of LSD1 is dynamically regulated via post-translational modifications and combinatorial associations with corepressors, such as ZNF198 or REST [ 19 , 20 ] . By integrating epigenetic modifications with signaling networks, LSD1 serves as a key spatiotemporal regulator of gene expression. Aberrant LSD1 activity contributes to tumorigenesis, viral latency, and other pathological processes [ 10 , 18 , 21 ] . LSD1 also promotes cancer progression via multiple epigenetic and non-epigenetic mechanisms [ 22 ] . In this study, we demonstrated that LSD1 promotes prostate cancer cell proliferation by upregulating PRAC1 expression. TAK-418 is a reversible brain-penetrating inhibitor that selectively targets LSD1. Structurally optimized to minimize the off-target effects on monoamine oxidases, TAK-418 exhibits superior safety to earlier LSD1 inhibitors, avoiding hematological toxicity [ 23 – 25 ] . By potently inhibiting the enzymatic activity of LSD1, TAK-418 blocks H3K4me1/me2 demethylation to reactivate the silenced neurodevelopmental genes that are critical for synaptic plasticity and memory formation [ 26 ] . Preclinical studies have demonstrated that TAK-418 can normalize aberrant epigenetic landscapes in models of neurodevelopmental disorders, including autism spectrum disorder and Kabuki syndrome [ 24 , 25 , 27 – 29 ] . In rodent models of autism spectrum disorder, TAK-418 rescues social deficits, repetitive behaviors, and cognitive inflexibility by restoring gene expression profiles in the brain regions linked to behavioral regulation [ 24 , 25 , 27 , 28 ] . In Kabuki syndrome, TAK-418 enhances hippocampal neurogenesis and alleviates memory impairments [ 29 ] . Although primarily investigated in neurodevelopmental disorders, the ability of TAK-418 to modulate cancer-related epigenetic plasticity makes it a promising candidate for precision oncology, particularly in tumors with LSD1 amplification or aberrant chromatin remodeling. In solid tumors, TAK-418 synergizes with DNA-demethylating agents or histone deacetylase inhibitors to enhance epigenetic reprogramming and overcome resistance to therapy. Early-phase trials explored its use in combination with immune checkpoint inhibitors, leveraging LSD1 inhibition to enhance tumor immunogenicity by upregulating endogenous retroviral elements and antigen presentation [ 30 ] . We found that TAK-418 inhibits prostate cancer cell proliferation by repressing PRAC1 expression. In conclusion, we found that LSD1 promotes prostate cancer cell proliferation by upregulating PRAC1 expression. Therefore, we propose PRAC1 or LSD1 inhibition as a promising therapeutic avenue for prostate cancer treatment. Materials and methods Cell culture and treatment LNCaP and DU145 cells were grown in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 1% antibiotics (100 U/mL penicillin and 100 µg/mL streptomycin sulfate; Sigma-Aldrich, Burlington, MA, USA) and 10% fetal bovine serum (FBS; Gibco, Waltham, MA, USA) at 37 ℃ in a humidified incubator with 5% CO2. To inhibit LSD1 activity, the cells were exposed to different concentrations of TAK-418 (MedChemExpress, Monmouth Junction, NJ, USA). To induce apoptosis, the cells were treated with 0.5 µM Docetaxel (MedChemExpress). Plasmids and siRNA transfection Small interfering RNAs (siRNAs) were purchased from GenScript (Nanjing, China). Cells were transfected with siRNAs using Lipofectamine 2000 (Life Technologies, Carlsbad, CA, USA) according to the manufacturer's instructions. The siRNA sequences are as follows: si-PRAC1-1: 5'-CATCTTACTACCTCCAAGAGT-3'; si-PRAC1-2:5'-GCTCAGCCTGTAATTCTGGAA-3'; siLSD1-1:5'-TGAATTAGCTGAAACACAATT-3'; siLSD1-2:5'-GCCTAGACATTAAACTGAATA-3'. Plasmid transfection was performed using Lipofectamine 8000 (Life Technologies, Carlsbad, CA, USA) according to the manufacturer's instructions. The PRAC1 expression plasmid was engineered by cloning the full-length open reading frame (ORF) of PRAC1 into the pCDH-CMV-MCS-EF1-Puro lentiviral vector. Reverse transcription and quantitative PCR Total RNA was isolated using TRIzol reagent (Life Technologies), incubated with RNase-free DNase I (Promega, Madison, WI, USA) for 30 min, and reverse-transcribed using the M-MLV Reverse Transcriptase (Promega). SYBR Green real-time PCR was performed using the ChamQ Universal SYBR® qPCR Master Mix (Vazyme Biotech Co., Ltd.) and ABI 7500 FAST sequence detection system (Life Technologies). The expression levels of all samples were normalized to the signal generated by glyceraldehyde-3-phosphate dehydrogenase. The primer sequences used are as follows: GAPDH: 5'-AACGGGAAGCTTGTCATCAA-3' and 5'-TGGACTCCACGACGTACTCA-3'; LSD1:5'-GTGGACGAGTTGCCACATTTC-3' and 5'-TGACCACAGCCATAGGATTCC-3'; PRAC1:5'-GCCCATTTCTCAGATCAAGG-3'and 5'-GGTCTCGCCCAGTAGATGTT-3'. Western blotting analysis Cells were lysed using RIPA buffer supplemented with protease inhibitor cocktail tablets (Roche, Basel, Switzerland), and the total protein content was measured using a BCA kit (Beyotime Biotechnology, Shanghai, China). 30–50 µg total protein were resolved using sodium dodecyl sulfate PAGE and transferred to a PVDF membrane (Bio-Rad Laboratories, Hercules, CA, USA). Blots were incubated with anti-GAPDH (Abcam, Waltham, MA 02453, USA) or anti-LSD1 (Abcam) antibodies, followed by incubation with HRP-conjugated secondary antibodies and detection using Clarity Western enhanced chemiluminescence substrate (Bio-Rad Laboratories). Cell proliferation assay Cells were seeded into 96-well plates (2 × 103 cells/well), and cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8; MedChemExpress, Monmouth Junction, NJ, USA) according to the manufacturer's instruction. Enzyme-Linked Immunosorbent Assays (ELISA) Given that the PRAC1 is 6 kDa, it is difficult to detect PRAC1 protein using western blotting. Therefore, we performed ELISA to measure PRAC1 protein expression in this study. To this end, we coated the wells of a microtiter plate with the anti-PRAC1 antibody (abx310485, Abbexa Ltd, Cambridge, UK) at a concentration of 10 µg/ml. After blocking, add 100 µl total cell lysate (1 µg/µl) to each well and incubate at room temperature for 2 h. Wash the plate 4 times with PBS, add 100 µl HRP-conjugated anti-PRAC1 antibody (abx310486, Abbexa Ltd) and incubate at room temperature for 2 h. Wash the plate 5 times with PBS, and prepare substrate working solution according to the manufacturer's instructions in the SignalUp™ Super Sensitive ELISA Assay Kit with Fluorescent HRP Substrate (Beyotime Biotechnology). Add 100 µl substrate working solution to each well and measure the fluorescence intensity using a microplate reader. Gene expression analysis For the RNA sequencing data from the TCGA-PRAD cohort, the expression levels of PRAC1and LSD1 and their expression correlation in prostate cancer tissues and non-cancerous prostate tissues were retrieved from the Gene Expression Profiling Interactive Analysis ( http://gepia.cancer-pku.cn/index.html ) database [ 31 ] . The genes that may regulate PRAC1 expression is identified by searching the GPSAdb database ( https://www.gpsadb.com/ ). Statistical analysis Data are presented as the mean ± SD of values from at least three independent experiments. Statistical analyses were performed using Student's t-test. A p value < 0.05 was considered to indicate statistically significant intergroup differences. Statistical analyses were conducted using GraphPad Prism 8 (GraphPad Software Inc., San Diego, CA, USA) (RRID: SCR_002798). Declarations Competing interests The authors declare no competing interests. Ethics declarations This study did not involve human or animal subjects, thus ethical approval was not required. Funding No funding was received for this research. Author Contribution YL performed the experiments, conducted data analysis, and drafted the manuscript.CL designed and supervised the study. All authors reviewed and approved the final manuscript. Acknowledgements We would like to express our gratitude to all those with whom we have had the pleasure of working on this and related projects. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7401472","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":510976826,"identity":"63916598-444d-4e30-b126-73fe7c9d1da3","order_by":0,"name":"Yang Liao","email":"","orcid":"","institution":"Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Liao","suffix":""},{"id":510976828,"identity":"08234cbc-72b2-4798-9658-315252f98ef1","order_by":1,"name":"Chuan Liu","email":"data:image/png;base64,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","orcid":"","institution":"Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Chuan","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-08-18 16:09:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7401472/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7401472/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-026-42928-8","type":"published","date":"2026-03-10T15:59:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90829946,"identity":"179f514d-7a0b-46b0-9b63-63c809bd4b3e","added_by":"auto","created_at":"2025-09-08 16:34:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":187075,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePRAC1\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e knockdown inhibits prostate cancer cell proliferation.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) \u003cem\u003ePRAC1\u003c/em\u003e mRNA levels in prostate cancer and non-cancerous prostate tissues. Data were downloaded from The Cancer Genome Atlas and the Genotype-Tissue Expression Portal. Red: prostate cancer tissue (n=492); gray: non-cancerous prostate tissue (n=192). (b–d) LNCaP cells were transfected with control or \u003cem\u003ePRAC1\u003c/em\u003e siRNA, and mRNA (b), and protein (c) levels of PRAC1 were determined using reverse transcription quantitative PCR and enzyme-linked immunosorbent assay, respectively, 48 h after transfection. (d) Cell proliferation assays were performed at different time points after transfection. Statistical analyses were performed using two-sided Student's \u003cem\u003et\u003c/em\u003e-tests; *p \u0026lt; 0.05, ** p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7401472/v1/c24a7d5488d0f9e4d42cdd0c.png"},{"id":90829948,"identity":"f0279d2f-7507-4bf0-a88d-b02eb609425c","added_by":"auto","created_at":"2025-09-08 16:34:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":132415,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe\u003c/strong\u003e \u003cstrong\u003eexpression of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eLSD1\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e is correlated with that of LSD1 in prostate cancer tissues.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) mRNA expression levels of \u003cem\u003ePRAC1\u003c/em\u003e are positively correlated with those of LSD1 in prostate cancer (n=492) and non-cancerous prostate tissues (n = 192). (b) LSD1 mRNA levels in prostate cancer tissues and non-cancerous prostate tissues. Data were downloaded from The Cancer Genome Atlas and the Genotype-Tissue Expression Portal. Red: prostate cancer tissue (n=492); gray: non-cancerous prostate tissue (n=192).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7401472/v1/513cd97561be222472de335e.png"},{"id":90829950,"identity":"679fd3dd-4446-455b-a9fe-60c81196d33d","added_by":"auto","created_at":"2025-09-08 16:34:22","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":219837,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLSD1 promotes \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003ePRAC1\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e expression in prostate cancer cells.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a–c) LNCaP cells were transfected with control or LSD1 siRNAs. (a) LSD1 and \u003cem\u003ePRAC1\u003c/em\u003e mRNA levels were determined using reverse transcription quantitative PCR 48 h after transfection, (b) LSD1 protein levels were determined using western blotting 48 h after transfection, and (c) PRAC1 protein levels were determined using enzyme-linked immunosorbent assay 48 h after transfection. \u003cem\u003ePRAC1\u003c/em\u003e mRNA (d) and protein (e) levels in LNCaP cells were determined using reverse transcription quantitative PCR and enzyme-linked immunosorbent assay, respectively, 72 h after treatment with different doses of TAK-418.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7401472/v1/40b82635b812df6f3f6c8f99.png"},{"id":90829957,"identity":"7f524d9e-46d0-4218-8639-33beb4db7435","added_by":"auto","created_at":"2025-09-08 16:34:22","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":601003,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eLSD1\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e knockdown represses prostate cancer cell proliferation by inhibiting \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003ePRAC1\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e expression.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLNCaP (a) and DU145 (b) cells were transfected with control or LSD1 siRNAs, and cell proliferation assays were performed at different time points after transfection. (c–f) LNCaP cells were transfected with LSD1 siRNAs or co-transfected with LSD1 siRNAs and \u003cem\u003ePRAC1\u003c/em\u003e-expressing plasmid; LSD1 protein (c) and mRNA (d) levels were determined using reverse transcription quantitative PCR and western blotting, respectively, at 48 h after transfection. (e) Protein levels of PRAC1 were determined using enzyme-linked immunosorbent assay 48 h after transfection, and (f) cell proliferation assays were performed at different time points after transfection. Statistical analysis was performed using two-sided Student’s \u003cem\u003et\u003c/em\u003e-tests; *p \u0026lt; 0.05, ** p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7401472/v1/b4393084516afe03892e9ffd.jpeg"},{"id":90833254,"identity":"3bcb9a50-90eb-4257-aee6-af9da5b5649b","added_by":"auto","created_at":"2025-09-08 17:06:22","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":215286,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTAK-418 represses prostate cancer cell proliferation by inhibiting \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003ePRAC1\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e expression.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLNCaP (a) and DU145 (b) cells were treated with different concentrations of TAK-418, and cell proliferation assays were performed at different time points. (c, d) LNCaP cells were transfected with \u003cem\u003ePRAC1\u003c/em\u003e-expressing plasmid or control plasmid and treated with or without 100 µM TAK-418. (c) Protein levels of PRAC1 were determined using enzyme-linked immunosorbent assay. (d) Cell proliferation assays were performed at different time points after transfection. Statistical analysis was performed using two-sided Student’s \u003cem\u003et\u003c/em\u003e-tests; *p \u0026lt; 0.05, ** p \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7401472/v1/0478b77fd4d8983767e04467.png"},{"id":104740290,"identity":"5286dacf-83df-4bd0-908b-a1ce19d54231","added_by":"auto","created_at":"2026-03-16 16:16:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2126752,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7401472/v1/2ff0ec12-602a-4667-bc79-0247cfe6f8ec.pdf"},{"id":90831114,"identity":"e4c4dc33-c9be-4d62-84ea-97d9812f5ed6","added_by":"auto","created_at":"2025-09-08 16:42:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":245989,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfiguresandlegends.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7401472/v1/fb7e4a83a38bc303aca11902.pdf"},{"id":90829947,"identity":"183ec2f0-9b2e-4604-a7c0-e5ff652950b8","added_by":"auto","created_at":"2025-09-08 16:34:22","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":252989,"visible":true,"origin":"","legend":"","description":"","filename":"Fulllengthwesternblotimages.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7401472/v1/b8d54b989bd115bf22a381f6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"LSD1 promotes prostate cancer cell proliferation by upregulating PRAC1 expression","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProstate cancer is a leading malignancy in men worldwide that contributes substantially to global male mortality. Although its incidence rates vary considerably across regions, with a higher prevalence in developed countries, emerging evidence suggests rising trends in developing nations owing to aging populations and lifestyle changes \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Prostate cancer poses substantial health risks, particularly for men aged\u0026thinsp;\u0026gt;\u0026thinsp;50 years, those with a family history of the disease, and individuals of African descent, who face disproportionately higher morbidity and mortality \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Although prostate cancer often progresses indolently, advanced stages can aggressively metastasize to bones and organs, causing debilitating complications \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Early detection via prostate-specific antigen screening can improve outcomes; however, current therapies are limited by issues of overtreatment and substantial impacts on quality of life, highlighting the need for more balanced clinical approaches \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Specifically, the development of innovative noninvasive biomarker detection techniques holds considerable promise for enhancing diagnostic precision, personalizing therapeutic interventions, and ultimately reducing both overtreatment and the burden of prostate cancer.\u003c/p\u003e\u003cp\u003e\u003cem\u003ePRAC\u003c/em\u003e encodes a 382 nucleotide RNA and a 6-kDa nuclear protein found in the prostate, rectum, and distal colon. The \u003cem\u003ePRAC\u003c/em\u003e gene is located on chromosome 17 at position 17q21, approximately 4 kb downstream of the homeodomain of Hoxb-13 \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. \u003cem\u003ePRAC1\u003c/em\u003e mRNA is a specific marker distinguishing semen from other bodily fluids \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. RNA in situ hybridization with a \u003cem\u003ePRAC1\u003c/em\u003e mRNA probe can detect exfoliated prostate cancer cells in urine \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Research has shown that \u003cem\u003ePRAC\u003c/em\u003e expression is lower in prostate cancer tissues than in benign prostatic hyperplasia tissues \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e and that \u003cem\u003ePRAC1\u003c/em\u003e plays an essential role in the maintenance and self-renewal of prostate epithelial stem cells \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. However, the role of \u003cem\u003ePRAC1\u003c/em\u003e in prostate cancer remains unclear.\u003c/p\u003e\u003cp\u003eTherefore, we investigated the role of \u003cem\u003ePRAC1\u003c/em\u003e in prostate cancer in this study. We found that \u003cem\u003ePRAC1\u003c/em\u003e expression is upregulated in prostate cancer tissues compared to that in non-cancerous prostate tissues, and \u003cem\u003ePRAC1\u003c/em\u003e knockdown inhibits prostate cancer cell proliferation. Moreover, we found that lysine-specific demethylase 1 (LSD1) promotes \u003cem\u003ePRAC1\u003c/em\u003e expression in prostate cancer cells and that LSD1 inhibition represses prostate cancer cell proliferation by downregulating \u003cem\u003ePRAC1\u003c/em\u003e expression. Our findings highlight \u003cem\u003ePRAC1\u003c/em\u003e as a novel therapeutic target for prostate cancer therapy.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003ePRAC1\u003c/b\u003e \u003cb\u003eknockdown inhibits prostate cancer cell proliferation\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo investigate the role of \u003cem\u003ePRAC1\u003c/em\u003e in prostate cancer, we compared the expression levels of \u003cem\u003ePRAC1\u003c/em\u003e in prostate cancer and non-cancerous prostate tissues using The Cancer Genome Atlas and the Genotype-Tissue Expression Portal. \u003cem\u003ePRAC1\u003c/em\u003e expression was upregulated in cancerous tissues compared to that in non-cancerous tissues (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Next, to investigate the effect of PRAC1 on cell proliferation, we knocked down \u003cem\u003ePRAC1\u003c/em\u003e in LNCaP and DU145 cells using two specific siRNAs (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb\u0026ndash;c and Supplementary Fig.\u0026nbsp;1a\u0026ndash;b). The MTS assay revealed that \u003cem\u003ePRAC1\u003c/em\u003e knockdown reduced cell proliferation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed and Supplementary Fig.\u0026nbsp;1c).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eLSD1 promotes\u003c/b\u003e \u003cb\u003ePRAC1\u003c/b\u003e \u003cb\u003eexpression in prostate cancer cells\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo investigate the mechanism underlying the upregulation of \u003cem\u003ePRAC1\u003c/em\u003e expression in prostate cancer cells, we searched the GPSAdb database to identify candidate genes that may regulate \u003cem\u003ePRAC1\u003c/em\u003e expression. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the knockdown of \u003cem\u003eIQGAP3\u003c/em\u003e, \u003cem\u003eHSF1\u003c/em\u003e, \u003cem\u003eHSF2\u003c/em\u003e, \u003cem\u003ePRRC2B\u003c/em\u003e, \u003cem\u003eLSD1\u003c/em\u003e, \u003cem\u003ePOU5F1\u003c/em\u003e, \u003cem\u003eARPIN\u003c/em\u003e, \u003cem\u003eRB1\u003c/em\u003e, \u003cem\u003eZZZ3\u003c/em\u003e, \u003cem\u003eTP53\u003c/em\u003e, \u003cem\u003eEWSR1\u003c/em\u003e, \u003cem\u003eALKBH5\u003c/em\u003e, \u003cem\u003eBUB3\u003c/em\u003e, or \u003cem\u003eRUVBL1\u003c/em\u003e led to the downregulation of \u003cem\u003ePRAC1\u003c/em\u003e expression. Additionally, we found that the mRNA expression levels of \u003cem\u003ePRAC1\u003c/em\u003e were positively correlated with those of LSD1 in prostate cancer and non-cancerous prostate tissues (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and that the mRNA expression levels of \u003cem\u003eLSD1\u003c/em\u003e were upregulated in prostate cancer tissues compared to those in non-cancerous prostate tissues (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). These data suggest that LSD1 may promote \u003cem\u003ePRAC1\u003c/em\u003e expression in prostate cancer tissues.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGenes that can regulate \u003cem\u003ePRAC1\u003c/em\u003e expression\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003epbgene\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCell line\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003elogFC\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e*R value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIQGAP3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003esiRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNTERA-2 cl.D1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-8.184598395\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9.16E-12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHSF1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003esiRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMCF 7.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-5.067259342\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.41E-12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHSF2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003esiRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMCF 7.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-4.474306955\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.60E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePRRC2B\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eshRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHEK293T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-3.979308572\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.44E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLSD1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eshRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eA-673\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-3.801029854\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.44E-121\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePOU5F1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eshRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eiPSCs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-3.787135872\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.15E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eARPIN\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eshRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLoVo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-3.173206952\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.95E-08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.089\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRB1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eshRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePC-3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-3.043327119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.58E-06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eZZZ3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003esiRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWA17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2.609872037\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.89E-11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTP53\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eshRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLNCaP clone FGC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2.574998038\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.52E-142\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.083\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRB1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eshRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLNCaP C4-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2.39566212\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.92E-97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEWSR1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003esiRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eA-673\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2.138551717\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.62E-50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eALKBH5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eko\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ehESCs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2.126864494\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.03E-09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBUB3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eshRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLNCaP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2.118112727\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.97E-30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEWSR1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003esiRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eA-673\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2.082121605\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6.99E-05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e-0.24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRUVBL1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eshRNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBPH-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e-2.061111305\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.22E-19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.089\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e* The expression correlation between \u003cem\u003ePRAC1\u003c/em\u003e and indicated genes in prostate\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003ecancer tissues and non-cancerous prostate tissues.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo investigate the regulatory role of LSD1 in \u003cem\u003ePRAC1\u003c/em\u003e expression, we knocked down \u003cem\u003eLSD1\u003c/em\u003e in prostate cancer cells and found that \u003cem\u003eLSD1\u003c/em\u003e knockdown inhibited \u003cem\u003ePRAC1\u003c/em\u003e expression (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea\u0026ndash;c and Supplementary Fig.\u0026nbsp;2a\u0026ndash;c). Furthermore, treatment with TAK-418, a specific LSD1 inhibitor, suppressed \u003cem\u003ePRAC1\u003c/em\u003e expression in a dose-dependent manner (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed\u0026ndash;e and Supplementary Fig.\u0026nbsp;2d\u0026ndash;e). Taken together, these data indicate that LSD1 promotes \u003cem\u003ePRAC1\u003c/em\u003e expression in prostate cancer cells.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTAK-418 represses prostate cancer cell proliferation by inhibiting\u003c/b\u003e \u003cb\u003ePRAC1\u003c/b\u003e \u003cb\u003eexpression\u003c/b\u003e\u003c/p\u003e\u003cp\u003eGiven that LSD1 promotes the expression of \u003cem\u003ePRAC1\u003c/em\u003e and inhibiting \u003cem\u003ePRAC1\u003c/em\u003e expression suppresses the proliferation of prostate cancer cells, we investigated whether LSD1 inhibition can repress prostate cancer cell proliferation by suppressing \u003cem\u003ePRAC1\u003c/em\u003e expression. The specific knockdown of \u003cem\u003eLSD1\u003c/em\u003e in prostate cancer cells significantly inhibited cellular proliferation (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea\u0026ndash;d), whereas \u003cem\u003ePRAC1\u003c/em\u003e overexpression partially rescued this effect (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ee\u0026ndash;f). Moreover, treatment with TAK-418 repressed prostate cancer cell proliferation (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea\u0026ndash;b), yet \u003cem\u003ePRAC1\u003c/em\u003e overexpression partially rescued this effect (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec\u0026ndash;d).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cem\u003ePRAC1\u003c/em\u003e is specifically expressed in prostate, rectal, and distal colon tissues and plays a critical role in the maintenance and self-renewal of prostate epithelial stem cells. Notably, \u003cem\u003ePRAC1\u003c/em\u003e mRNA serves as a semen-specific biomarker for forensic identification, enabling the noninvasive detection of exfoliated prostate cancer cells in urine \u003csup\u003e[\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. In this study, we found that \u003cem\u003ePRAC1\u003c/em\u003e expression is upregulated in prostate cancer cells, and that \u003cem\u003ePRAC1\u003c/em\u003e knockdown represses prostate cancer cell proliferation. These findings identify \u003cem\u003ePRAC1\u003c/em\u003e as a potential therapeutic target in prostate cancer.\u003c/p\u003e\u003cp\u003eLSD1 is an evolutionarily conserved histone demethylase that dynamically regulates the chromatin structure and gene transcription by removing methyl groups from histone H3 lysine residues at positions 4 (H3K4) and 9 (H3K9) via oxidative reactions. As a core component of multiprotein complexes (e.g., CoREST/histone deacetylase complexes), LSD1 mediates transcriptional repression via H3K4 demethylation, and participates in stem cell differentiation, embryonic development, and hematopoietic cell maturation \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. In nuclear receptor signaling pathways such as androgen receptor signaling, LSD1 removes repressive H3K9 methylation marks to activate target gene transcription and promote prostate cancer cell proliferation \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. LSD1 also exhibits non-histone substrate specificity, regulating the methylation status of proteins such as p53 and DNMT1 to influence the DNA damage response and DNA methylation homeostasis \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. The activity of LSD1 is dynamically regulated via post-translational modifications and combinatorial associations with corepressors, such as ZNF198 or REST \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. By integrating epigenetic modifications with signaling networks, LSD1 serves as a key spatiotemporal regulator of gene expression. Aberrant LSD1 activity contributes to tumorigenesis, viral latency, and other pathological processes \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. LSD1 also promotes cancer progression via multiple epigenetic and non-epigenetic mechanisms \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. In this study, we demonstrated that LSD1 promotes prostate cancer cell proliferation by upregulating \u003cem\u003ePRAC1\u003c/em\u003e expression.\u003c/p\u003e\u003cp\u003eTAK-418 is a reversible brain-penetrating inhibitor that selectively targets LSD1. Structurally optimized to minimize the off-target effects on monoamine oxidases, TAK-418 exhibits superior safety to earlier LSD1 inhibitors, avoiding hematological toxicity \u003csup\u003e[\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. By potently inhibiting the enzymatic activity of LSD1, TAK-418 blocks H3K4me1/me2 demethylation to reactivate the silenced neurodevelopmental genes that are critical for synaptic plasticity and memory formation \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Preclinical studies have demonstrated that TAK-418 can normalize aberrant epigenetic landscapes in models of neurodevelopmental disorders, including autism spectrum disorder and Kabuki syndrome \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. In rodent models of autism spectrum disorder, TAK-418 rescues social deficits, repetitive behaviors, and cognitive inflexibility by restoring gene expression profiles in the brain regions linked to behavioral regulation \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. In Kabuki syndrome, TAK-418 enhances hippocampal neurogenesis and alleviates memory impairments \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. Although primarily investigated in neurodevelopmental disorders, the ability of TAK-418 to modulate cancer-related epigenetic plasticity makes it a promising candidate for precision oncology, particularly in tumors with LSD1 amplification or aberrant chromatin remodeling. In solid tumors, TAK-418 synergizes with DNA-demethylating agents or histone deacetylase inhibitors to enhance epigenetic reprogramming and overcome resistance to therapy. Early-phase trials explored its use in combination with immune checkpoint inhibitors, leveraging LSD1 inhibition to enhance tumor immunogenicity by upregulating endogenous retroviral elements and antigen presentation \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. We found that TAK-418 inhibits prostate cancer cell proliferation by repressing \u003cem\u003ePRAC1\u003c/em\u003e expression.\u003c/p\u003e\u003cp\u003eIn conclusion, we found that LSD1 promotes prostate cancer cell proliferation by upregulating \u003cem\u003ePRAC1\u003c/em\u003e expression. Therefore, we propose \u003cem\u003ePRAC1\u003c/em\u003e or LSD1 inhibition as a promising therapeutic avenue for prostate cancer treatment.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eCell culture and treatment\u003c/h2\u003e\u003cp\u003eLNCaP and DU145 cells were grown in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 1% antibiotics (100 U/mL penicillin and 100 \u0026micro;g/mL streptomycin sulfate; Sigma-Aldrich, Burlington, MA, USA) and 10% fetal bovine serum (FBS; Gibco, Waltham, MA, USA) at 37 ℃ in a humidified incubator with 5% CO2. To inhibit LSD1 activity, the cells were exposed to different concentrations of TAK-418 (MedChemExpress, Monmouth Junction, NJ, USA). To induce apoptosis, the cells were treated with 0.5 \u0026micro;M Docetaxel (MedChemExpress).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePlasmids and siRNA transfection\u003c/h3\u003e\n\u003cp\u003eSmall interfering RNAs (siRNAs) were purchased from GenScript (Nanjing, China). Cells were transfected with siRNAs using Lipofectamine 2000 (Life Technologies, Carlsbad, CA, USA) according to the manufacturer's instructions. The siRNA sequences are as follows: si-PRAC1-1: 5'-CATCTTACTACCTCCAAGAGT-3'; si-PRAC1-2:5'-GCTCAGCCTGTAATTCTGGAA-3'; siLSD1-1:5'-TGAATTAGCTGAAACACAATT-3'; siLSD1-2:5'-GCCTAGACATTAAACTGAATA-3'.\u003c/p\u003e\u003cp\u003ePlasmid transfection was performed using Lipofectamine 8000 (Life Technologies, Carlsbad, CA, USA) according to the manufacturer's instructions. The PRAC1 expression plasmid was engineered by cloning the full-length open reading frame (ORF) of PRAC1 into the pCDH-CMV-MCS-EF1-Puro lentiviral vector.\u003c/p\u003e\n\u003ch3\u003eReverse transcription and quantitative PCR\u003c/h3\u003e\n\u003cp\u003eTotal RNA was isolated using TRIzol reagent (Life Technologies), incubated with RNase-free DNase I (Promega, Madison, WI, USA) for 30 min, and reverse-transcribed using the M-MLV Reverse Transcriptase (Promega). SYBR Green real-time PCR was performed using the ChamQ Universal SYBR\u0026reg; qPCR Master Mix (Vazyme Biotech Co., Ltd.) and ABI 7500 FAST sequence detection system (Life Technologies). The expression levels of all samples were normalized to the signal generated by glyceraldehyde-3-phosphate dehydrogenase. The primer sequences used are as follows: GAPDH: 5'-AACGGGAAGCTTGTCATCAA-3' and 5'-TGGACTCCACGACGTACTCA-3'; LSD1:5'-GTGGACGAGTTGCCACATTTC-3' and 5'-TGACCACAGCCATAGGATTCC-3'; PRAC1:5'-GCCCATTTCTCAGATCAAGG-3'and 5'-GGTCTCGCCCAGTAGATGTT-3'.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eWestern blotting analysis\u003c/h2\u003e\u003cp\u003eCells were lysed using RIPA buffer supplemented with protease inhibitor cocktail tablets (Roche, Basel, Switzerland), and the total protein content was measured using a BCA kit (Beyotime Biotechnology, Shanghai, China). 30\u0026ndash;50 \u0026micro;g total protein were resolved using sodium dodecyl sulfate PAGE and transferred to a PVDF membrane (Bio-Rad Laboratories, Hercules, CA, USA). Blots were incubated with anti-GAPDH (Abcam, Waltham, MA 02453, USA) or anti-LSD1 (Abcam) antibodies, followed by incubation with HRP-conjugated secondary antibodies and detection using Clarity Western enhanced chemiluminescence substrate (Bio-Rad Laboratories).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCell proliferation assay\u003c/h3\u003e\n\u003cp\u003eCells were seeded into 96-well plates (2 \u0026times; 103 cells/well), and cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8; MedChemExpress, Monmouth Junction, NJ, USA) according to the manufacturer's instruction.\u003c/p\u003e\n\u003ch3\u003eEnzyme-Linked Immunosorbent Assays (ELISA)\u003c/h3\u003e\n\u003cp\u003eGiven that the PRAC1 is 6 kDa, it is difficult to detect PRAC1 protein using western blotting. Therefore, we performed ELISA to measure PRAC1 protein expression in this study. To this end, we coated the wells of a microtiter plate with the anti-PRAC1 antibody (abx310485, Abbexa Ltd, Cambridge, UK) at a concentration of 10 \u0026micro;g/ml. After blocking, add 100 \u0026micro;l total cell lysate (1 \u0026micro;g/\u0026micro;l) to each well and incubate at room temperature for 2 h. Wash the plate 4 times with PBS, add 100 \u0026micro;l HRP-conjugated anti-PRAC1 antibody (abx310486, Abbexa Ltd) and incubate at room temperature for 2 h. Wash the plate 5 times with PBS, and prepare substrate working solution according to the manufacturer's instructions in the SignalUp\u0026trade; Super Sensitive ELISA Assay Kit with Fluorescent HRP Substrate (Beyotime Biotechnology). Add 100 \u0026micro;l substrate working solution to each well and measure the fluorescence intensity using a microplate reader.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eGene expression analysis\u003c/h2\u003e\u003cp\u003eFor the RNA sequencing data from the TCGA-PRAD cohort, the expression levels of PRAC1and LSD1 and their expression correlation in prostate cancer tissues and non-cancerous prostate tissues were retrieved from the Gene Expression Profiling Interactive Analysis (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://gepia.cancer-pku.cn/index.html\u003c/span\u003e\u003cspan address=\"http://gepia.cancer-pku.cn/index.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) database \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. The genes that may regulate PRAC1 expression is identified by searching the GPSAdb database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.gpsadb.com/\u003c/span\u003e\u003cspan address=\"https://www.gpsadb.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eData are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of values from at least three independent experiments. Statistical analyses were performed using Student's t-test. A p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate statistically significant intergroup differences. Statistical analyses were conducted using GraphPad Prism 8 (GraphPad Software Inc., San Diego, CA, USA) (RRID: SCR_002798).\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eEthics declarations\u003c/h2\u003e\u003cp\u003eThis study did not involve human or animal subjects, thus ethical approval was not required.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eNo funding was received for this research.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYL performed the experiments, conducted data analysis, and drafted the manuscript.CL designed and supervised the study. All authors reviewed and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eWe would like to express our gratitude to all those with whom we have had the pleasure of working on this and related projects.\u003c/p\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eData availability\u003c/h2\u003e\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\u003c/div\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiegel, D. A., O'Neil, M. E., Richards, T. B., Dowling, N. F. \u0026amp; Weir, H. K. Prostate Cancer Incidence and Survival, by Stage and Race/Ethnicity - United States, 2001\u0026ndash;2017. \u003cem\u003eMMWR Morb. Mortal. 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However, the role of \u003cem\u003ePRAC1\u003c/em\u003e in prostate cancer is unclear. In this study, we found that \u003cem\u003ePRAC1\u003c/em\u003e expression is upregulated in prostate cancer cells and that \u003cem\u003ePRAC1\u003c/em\u003e knockdown represses the proliferation of prostate cancer cells. Moreover, lysine-specific demethylase 1 (LSD1) promoted prostate cancer cell proliferation by upregulating \u003cem\u003ePRAC1\u003c/em\u003e expression. TAK-418, an LSD1 inhibitor, suppressed prostate cancer cell proliferation by downregulating \u003cem\u003ePRAC1\u003c/em\u003e expression. The results of this study highlight \u003cem\u003ePRAC1\u003c/em\u003e or LSD1 inhibition as promising avenues for prostate cancer treatment.\u003c/p\u003e","manuscriptTitle":"LSD1 promotes prostate cancer cell proliferation by upregulating PRAC1 expression","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-08 16:34:18","doi":"10.21203/rs.3.rs-7401472/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-27T12:23:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-17T18:41:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-13T01:18:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"41045092478967936741406354119859837862","date":"2025-09-05T21:31:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"186833853541601414884928517891017452747","date":"2025-09-05T02:32:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"245816074567398752224653981575298537829","date":"2025-09-04T20:00:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"26261319344340529075146274216663025540","date":"2025-09-03T02:19:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-02T19:52:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-02T19:46:25+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-02T12:06:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-31T11:27:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-08-31T11:25:01+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":"6131ead3-b9b1-4f1b-b0c2-0a2307a0eeff","owner":[],"postedDate":"September 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":54281202,"name":"Biological sciences/Cancer"},{"id":54281203,"name":"Biological sciences/Cell biology"},{"id":54281204,"name":"Health sciences/Oncology"},{"id":54281205,"name":"Health sciences/Urology"}],"tags":[],"updatedAt":"2026-03-16T16:11:46+00:00","versionOfRecord":{"articleIdentity":"rs-7401472","link":"https://doi.org/10.1038/s41598-026-42928-8","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-03-10 15:59:23","publishedOnDateReadable":"March 10th, 2026"},"versionCreatedAt":"2025-09-08 16:34:18","video":"","vorDoi":"10.1038/s41598-026-42928-8","vorDoiUrl":"https://doi.org/10.1038/s41598-026-42928-8","workflowStages":[]},"version":"v1","identity":"rs-7401472","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7401472","identity":"rs-7401472","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}