{"paper_id":"e35d1377-e989-4cfd-8f27-87bbfefa8af4","body_text":"Cancer, in its essence, encompasses more than 100 distinct malignant diseases that manifest in different tissues throughout the human body [ 1 ,  2 ]. The elevated mortality rates linked to cancer are, in part, attributable to deficient early detection modalities and imprecise diagnostic instruments. Therefore, precise cancer diagnosis and prognosis estimation are crucial to improving patient survival rates. The prevailing cancer biomarkers, predominantly comprised of protein or peptide‐based entities like glycoproteins, often demonstrate fluctuations in their tissue or blood levels, serving as potential indicators for disease progression, including cancer [ 3 ].\nAn increasing body of research has substantiated the pivotal role of epigenetic alterations in tumorigenesis and cancer progression. Epigenetic processes are crucial for maintaining proper growth, development and gene control in various body systems [ 4 ]. When these mechanisms become disrupted, they can alter gene function, leading to pathological conditions such as cancer. So, tumorigenesis cannot be solely attributed to genetic modifications, as it also encompasses epigenetic transformations, including DNA methylation [ 5 ]. This covalent alteration can impede gene transcription by either obstructing the interaction between a transcription factor and its corresponding binding sites or recruiting methylated binding domain proteins that facilitate the suppression of gene expression [ 6 ].\nDNMT1  is an enzymatic catalyst that establishes DNA methylation patterns throughout cellular differentiation and development.  UHRF1  is a cofactor of  DNMT1  and binds directly to DNMT1 via its N‐terminal ubiquitin‐like domain (UBL). UHRF1 RING domain catalysed the binding of  DNMT1  to ubiquitinated histone H3, ensuring subnuclear localization of  DNMT1  and maintenance of DNA methylation [ 7 ]. Multiple investigations have demonstrated its pivotal contribution to the pathogenesis of cancer [ 8 ]. In this regard, Zhang et al. examined the correlation between  DNMT1  and aberrant methylation patterns of tumour suppressor genes (TSGs) and their association with the malignant phenotype observed in cervical cancer (CC). Their findings disclosed that the  DNMT1  methylation status could impact the activity of various crucial TSGs during the development of cervical tumours. Consequently, targeting  DNMT1  methylation holds promise as a viable therapeutic approach for treating CC [ 9 ]. Furthermore,  DNMT1 ‐mediated effects in carcinogenesis may occur through the regulation of cell cycle‐ and apoptosis‐related genes. Notably,  DNMT1  silencing has been shown to increase Bax expression while decreasing  Bcl‐2  and  CCND1 / 2  in AN3CA cells, suggesting the potential of  DNMT1  in endometrial carcinoma (EC) therapy [ 10 ]. Thereby, among the numerous epigenetic regulators associated with cancer, DNMT1 has been identified as a key enzyme, owing to its fundamental role in maintaining cellular methyltransferase activity, regulating both global and gene‐specific demethylation, and the reactivation of TSGs in human cancer cells [ 11 ]. In this manner, exploring the function of DNMT1 in cancer presents a valuable opportunity to increase our understanding of tumour biology and to identify potential therapeutic targets.\nRecent extensive research emphasises the importance of ncRNA molecules in governing the function of  DNMT1 . In this regard, DACOR1, a long non‐coding RNA (lncRNA), has been shown to activate tumour‐suppressor pathways and function as a regulator of cellular growth suppression. In terms of mechanism, DACOR1 markedly reduced the expression of cystathionine β‐synthase, a critical methyl donor in DNA methylation. Collectively, dysregulation of DNMT1‐associated lncRNAs plays a critical role in driving abnormal DNA methylation patterns and gene expression in colon tumorigenesis [ 12 ]. Furthermore, recent investigations offer valuable insights into the intercommunication and mechanisms involved in regulating  DNMT1  by ncRNA. This observation underscores the extensive engagement of ncRNAs and their interplay with crucial epigenetic modifiers, such as  DNMT1 , governing the expression of numerous target genes.\n\nHuman Genome Project Completion has unveiled that approximately 1.5% of the human genome is constituted by protein‐coding genes [ 13 ]. Indeed, the Encyclopaedia of DNA Elements (ENCODE) and the Functional Annotation of the Mammalian Genome (FANTOM), two prominent collaborative initiatives, have provided evidence indicating that a significant portion of the genome undergoes transcription and generates a diverse array of ncRNAs [ 14 ]. Presently, there is a prevailing belief that the level of intricacy exhibited by a species demonstrates a stronger correlation with the quantity of ncRNAs rather than the number of protein‐coding genes [ 15 ]. NcRNAs are indispensable agents in regulating essential cellular functions spanning all biological kingdoms. They actively govern diverse aspects of gene expression, including transcription and translation processes, thereby profoundly influencing genome organisation and stability [ 16 ]. Mounting evidence suggests that ncRNAs exert a diverse range of mechanisms, such as transcriptional processes, stability of messenger RNA (mRNA), post‐translational modifications, modulation of chromosome structure and RNA splicing. Notably, miRNA, lncRNA and circular RNA (circRNA) are among the extensively investigated ncRNAs. The subsequent section provides a more comprehensive elucidation of these well‐studied ncRNA types.\nMiRNAs represent a class of diminutive RNA molecules, typically about 22 nucleotides in length, which can exert negative post‐transcriptional regulation over their target gene expression [ 17 ].  RNA polymerase II (Pol II)  transcribes these miRNAs into primary transcripts, which undergo processing within the cellular nucleus by the RNase III  Drosha  and  DGCR8  (microprocessor complex) to form precursor miRNAs [ 18 ]. Precursor miRNAs exhibit a configuration characterised by imperfect stem loops and undergo translocation to the cytoplasm facilitated by  Exportin‐5  [ 19 ]. Within the cytoplasmic compartment, these precursor miRNAs undergo additional processing by the RNase III Dicer to attain their ultimate functional mature miRNA form. MiRNAs exert their regulatory function by forming complexes with their target mRNAs, resulting in the downregulation of mRNA stabilities and translation. In cases where the miRNA exhibits complete complementarity with its target mRNA, it can initiate the degradation of the targeted mRNA molecule. MiRNAs can also engage with their targets through partial complementarity, frequently observed in the 3′ UTR regions of mRNAs. This interaction results in the translational suppression of the target genes by a partially understood mechanism that necessitates further investigation for complete elucidation [ 20 ]. Using post‐transcriptional gene silencing (PTGS) and mRNA degradation, miRNAs can govern the epigenome, thereby inducing downregulation of critical epigenetic modifiers and orchestrating alterations in the chromatin landscape [ 21 ]. Prominent instances of epigenetic factors engaging with miRNAs encompass histone deacetylases ( HDACs ), histone methyltransferases ( HMTs ) and DNA methyltransferases ( DNMTs ). Apart from the miRNAs that hold the capacity to regulate the epigenome, it is noteworthy that the expression of these miRNAs can, in turn, be subject to regulation through epigenetic modifications. For instance, CpG islands, typically prevalent at gene promoters, are likewise present in around half of all miRNA genes, rendering them susceptible to abnormal DNA methylation and consequent dysregulation of gene expression [ 22 ]. These epigenetic modifications can induce either the downregulation or upregulation of miRNA expressions and, these altered expression patterns have been linked to various stages of tumorigenesis. In this regard, Hu et al. conducted qRT‐PCR and genomic bisulfite sequencing to examine the epigenetic silencing of miR‐484 in CC. They observed that the insufficiency of  DNMT1 , which  EZH2  recruits, led to a decline in CpG methylation within the promoter region miR‐484, elevating miR‐484 expression levels. They concluded that miR‐484 was reduced due to  DNMT1 ‐mediated hypermethylation occurring in its promoter region, and this molecular event contributes to its role as a tumour suppressor in CC [ 23 ]. These findings demonstrated a reciprocal relationship between  DNMT1  and miRNAs in human cancer (Figure  1 ).\nA schematic representation of the direct relationship between DNMT1 and miRNAs. The illustration portrays how specific miRNAs target DNMT1 mRNA, leading to the inhibition of its transcriptional activity. Conversely, DNMT1 exerts control by methylating the genes encoding these miRNAs, thereby impeding their own transcription. This bidirectional modulation highlights the intricate regulatory crosstalk between DNMT1 and miRNAs in epigenetic regulation.\nLncRNAs, encompassing sequences exceeding 200 nucleotides, participate in many physiological and pathological processes, emphasising their significant involvement in cancer development [ 24 ]. LncRNAs exert regulatory control over tumour progression by actively engaging in gene expression, drug resistance and metastasis [ 25 ]. Remarkably, contemporary investigations have unveiled the multifaceted capacity of lncRNAs in orchestrating DNA methylation processes [ 12 ]. While the prevalence of this model remains uncertain in the present era, a diverse array of lncRNAs has been documented to engage  DNMTs  and govern the expression of target genes, thus assuming pivotal functions in various biological processes, including but not limited to osteoarthritis, neural differentiation, cardiovascular diseases, adipogenesis, mesoderm commitment, mental disorders, muscle regeneration and different cancer types [ 26 ]. Furthermore, certain lncRNAs have been demonstrated to act as sequestering agents for  DNMT , thereby exerting a negative regulatory influence on DNA methylation. In this regard, nuclear paraspeckle assembly transcript 1 ( NEAT1 ) directly interacts with  DNMT1 , leading to the subsequent suppression of P53 and cyclic GMP‐AMP synthase stimulator of interferon genes ( cGAS / STING ) expression in lung cancer. So,  NEAT1 , by interacting with DNMT1, inhibits the  cGAS/STING  pathway, thereby regulating cytotoxic T cell infiltration in lung cancer [ 27 ]. Furthermore, a recent functional investigation also substantiated the interaction between  lncRNA ATB  and  DNMT1 , stabilising  DNMT1  expression. Furthermore,  ATB  facilitated the association of  DNMT1  with  p53 . Importantly, heightened expression of  lncRNA ATB  expedited the proliferative and migratory capabilities of renal cell carcinoma (RCC) cells while concurrently hindering cell apoptosis. This effect is attributed to the  p53  reduction, which is facilitated by the binding of  ATB  to  DNMT1  [ 28 ]. Importantly, substantial evidence demonstrates that lncRNAs exert control over the expression of DNMTs and Ten‐Eleven Translocation enzymes ( TETs ) at various regulatory levels to modulate DNA methylation processes. Studies have reported that lncRNAs can suppress or promote DNMT expression, thus assuming crucial roles in cancer development. In this regard,  lncRNA GAS5  directly interacts with  EZH2 , consequently facilitating the assembly of the polycomb repressive complex 2 ( PRC2 ). This molecular event, in turn, leads to the transcriptional suppression of  DNMT1  [ 29 ]. Therefore, lncRNAs, by regulating  DNMT1 , are involved in the epigenetic process.\n\nDNMT1 , a considerable protein consisting of 1616 amino acids and featuring multiple domains, is intricately governed by intramolecular regulations that precisely restrict its functionality to hemimethylated DNA sites [ 30 ]. Notably, during DNA replication,  DNMT1  plays a pivotal role in propagating DNA methylation.  DNMT1  is classified as a class I methyltransferase family member, characterised by its possession of a conserved catalytic core known as the Rossmann fold. This core structure comprises a mixed seven‐stranded β‐sheet, bordered by three α‐helices on each side [ 31 ]. This enzyme facilitates the methylation reaction using an S‐adenosyl‐L‐methionine (AdoMet) —dependent mechanism. Within its catalytic core, it contains critical motifs responsible for both enzymatic catalysis and binding with the cofactor. An additional subdomain, the target recognition domain (TRD), is situated between the central β‐sheet and the final α‐helix of the catalytic core [ 32 ,  33 ]. Furthermore, extensive research spanning several decades has examined the structure and function of  DNMT1 . Kikuchi et al. explored the structural characteristics of human  DNMT1  (amino acid residues: 351–1616) through cryogenic electron microscopy (cryo‐EM). Their investigation involved the stimulation of  DNMT1  by the H3Ub2 tail and its formation of an intermediate complex alongside a hemimethylated DNA analogue. They present the cryo‐EM structure of the interaction between human  DNMT1  and its native co‐activators, namely hemimethylated DNA and ubiquitinated histone H3. They discover a previously unexplored linker positioned between the Replication‐Foci Targeting Sequence (RFTS) and CXXC domains, which serve as a critical mediator for activation. Concurrent with this phenomenon, there is a substantial reconfiguration of the inhibitory RFTS and CXXC domains, facilitating the enzyme to attain its complete functional capacity. The findings offer a basis for understanding how  DNMT1  is activated, which has implications for basic research and drug development [ 34 ]. Over the last 20 years, evidence has progressively linked the involvement and importance of  DNMT1  in tumorigenesis, aggressiveness and treatment response of human cancers. In this context, Liu et al. revealed that in breast cancer (BC), DNMT1‐mediated hypermethylation of the  FOXO3a  promoter results in the suppression of  FOXO3a expression .  FOXO3a  exhibits functional interrelation with the repression of  FOXM1/SOX2  signalling, thereby leading to the consequential suppression of BCSC properties and tumorigenicity. Moreover, their investigation revealed that  SOX2  exerts direct transactivation on  DNMT1  expression, consequently inducing alterations in the methylation landscape. This, in turn, creates a feedback loop that leads to the inhibition of  FOXO3a  expression. Additionally, they unveiled that the suppression of DNMT activity resulted in the suppression of tumour growth by modulating the  FOXO3a/FOXM1/SOX2  signalling axis in BC. From a clinical perspective, a notable and statistically significant inverse relationship was observed between the expression levels of  FOXO3a  and  FOXM1/SOX2/DNMT1 . Furthermore, instances of diminished  FOXO3a  expression or elevated levels of  FOXM1 ,  SOX2  and  DNMT1  were indicative of an unfavourable prognosis in BC patients. Their findings present compelling evidence regarding the significant involvement of the  DNMT1 / FOXO3a / FOXM1 / SOX2  pathway in regulating BCSC properties. This underscores the potential for identifying therapeutic targets for BC treatment based on these mechanistic insights [ 35 ]. Multiple studies have demonstrated that ncRNAs exhibit the ability to directly interact with  DNMT1 , resulting in alterations within the cancer cell's epigenome. This has the potential to reveal a previously unknown mechanism that accounts for the substantial alterations in the epigenome observed across different types of tumours. In this regard,  lncRNA KIF9‐AS1  is critical in regulating  RAI2  expression, mainly through the recruitment of  DNMT1  and subsequent modulation of  RAI2  DNA methylation. Additionally, upregulation of  RAI2  hindered the migration and proliferation while enhancing apoptosis in HCC cells. Further in vivo experimentation revealed that  KIF9‐AS1  silencing inhibits subcutaneous tumour formation. Thereby,  KIF9‐AS1  actively promotes HCC growth by facilitating  DNMT1 ‐mediated promotion of  RAI2  DNA methylation [ 36 ](Figure  2 ).\nA schematic representation of DNMT1 location, expression and functioning in human cancer. (A) Depiction of DNMT1 transcriptional processes followed by (B) translation leading to its expression. (C) Highlighting DNMT1's functional impact on chromatin structure regulation. (D) Illustrating the downstream effects of epigenetic changes mediated by DNMT1 on key biological features of cancer cells, encompassing proliferation, apoptosis resistance, angiogenesis and metastasis. This comprehensive portrayal underscores the pivotal involvement of DNMT1 across multiple stages of cancer development and progression.\n\nHepatocellular carcinoma (HCC) represents the predominant form of primary liver malignancies globally, constituting approximately 90% of cases. This particular type of cancer stands as a prominent contributor to malignancy in humans, exhibiting substantial rates of both morbidity and mortality [ 37 ]. Therefore, a comprehensive understanding of the pathogenetic mechanisms underlying HCC and its regulatory processes is crucial for the effective management and treatment strategies employed for HCC.\nMiRNA‐148 (MiR‐148)  and  miR‐152  belong to the  miR‐148/152  family, which comprises  miR‐152 ,  miR‐148 b  and  miR‐148a . The members of this family may serve as valuable prognostic indicators and/or promising therapeutic targets for addressing diverse cancer types [ 38 ]. Recently, the functional importance of HBV X protein (HBx) in hepatocarcinogenesis has been explored. It was disclosed that  RIZ1  expression is significantly reduced within HCC tissues and is negatively regulated by  DNMT1  and recombinant HBV X protein (HBx). Also,  DNMT1  protein could bind to the promoter region of the  RIZ1  gene, and silencing  DNMT1  led to a decrease in the presence of methylated CpG sites within the genomic region associated with  RIZ1 . Notably, HBX recombinant plays a crucial role in  DNMT1  binding to the  RIZ1  gene promoter. Further mechanistic investigations demonstrated that the HBx upregulation led to a notable reduction in miR‐152 expression. Conversely, miR‐152 upregulation, primarily through direct targeting of  DNMT1 , resulted in the downregulation of  DNMT1  expression. So, HBx, by reducing miR‐152 expression, increases  DNMT1  expression. Significantly, this interplay between  miR‐152  and  DNMT1  has contributed, at least partially, to the epigenetic inactivation of  RIZ1 . Thereby, HBx primarily suppressed  RIZ1  expression in HCC by lowering  miR ‐ 152  levels and increasing  DNMT1  levels, thus presenting a novel mechanism for the inactivation of  RIZ1  [ 39 ].\nmiR‐148a  functions as a miRNA with tumour‐suppressive properties, exerting a critical influence on the initiation and progression of HCC [ 40 ]. According to recent exploration, the silencing of miR‐148a in HCC cell lines is attributed to the hypermethylation of its CpG Island, and  DNMT1  upregulation serves as a causative factor behind the hypermethylation occurring at the  miR‐148a  promoter region. Interestingly, there is an inverse correlation between the expression of  DNMT1 , a target gene of  miR‐148a , and the expression levels of  miR‐148a  within HCC cells. Significantly,  miR‐148a  upregulation markedly suppresses HCC cell cycle progression and cell proliferation. These results propose an innovative regulatory circuit involving  miR‐148a  and  DNMT1 , implying that  miR‐148a  functions as a tumour suppressor during hepatocellular carcinogenesis [ 41 ].\nThe differential expression of  miR‐185  has been observed to occur frequently in samples obtained from cancer patients.  MiR‐185  significantly downregulated in HCC tissues compared to the adjacent nonneoplastic liver parenchyma. Further, miR‐185 diminished in HCC cells as compared to primary hepatocytes. Functional experimentation disclosed that introducing exogenous  miR‐185  into HCC cells inhibited cellular proliferation and invasion in vitro and impeded tumour growth in  SCID  mice. Additionally, it was observed that  miR‐185  exhibits a direct targeting effect on  DNMT1  within HCC cells. Furthermore, upregulation of  miR‐185  reduced  DNMT1  protein levels in HCC cells. Significantly, the upregulation of  DNMT1  hindered the suppressive effects of  miR‐185  on HCC cell proliferation and invasion, thus implying the involvement of  DNMT1  in the inhibitory mechanism of  miR‐185  on HCC growth. Notably, the upregulation of  miR‐185  resulted in a decrease in  PTEN  promoter DNA methylation and an increase in  PTEN  expression, consequently leading to the suppression of Akt phosphorylation. However, the observed effects were somewhat counteracted by the upregulation of  DNMT1 . Thereby,  miR‐185  hinders the proliferation of HCC cells by selectively interacting with  DNMT1 , thereby inducing  PTEN  expression while inhibiting Akt activity [ 42 ].\nMicroRNA‐378a , comprising  miR‐378a‐3p  and  miR‐378a‐5p , is derived from the  PPARGC1B  gene. It plays a critical role in tumour development and is an autonomous prognostic indicator for different types of malignant neoplasms [ 43 ].  MiR‐378a  is considerably downregulated in HCC and corresponds to elevated microvascular density (MVD). Furthermore, the reduced expression of  miR‐378a‐3p  is a prognostic indicator for a diminished survival time among HCC patients. In addition, suppression of  miR‐378a‐3p  led to a noteworthy augmentation in vitro and in vivo angiogenesis. Furthermore, a direct association exists between miR‐378a‐3p and  TNF receptor‐associated factor 1 (TRAF1) . This interaction led to the subsequent modulation of NF‐κB signalling, ultimately deregulating secreted  VEGF . Mechanistic analysis unveiled that the downregulation of  miR‐378a‐3p  is attributed to the hypermethylation mediated by  DNMT1 . Moreover,  p65  instigated a positive feedback loop that enhanced the expression of  DNMT1 , thereby facilitating excessive methylation of the  miR‐378a‐3p  promoter region. In this manner, a positive feedback loop involving  DNMT1 ,  miR‐378a‐3p ,  TRAF1  and  NF‐κB  plays a critical role in HCC cells, suggesting its potential as a viable therapeutic target for HCC [ 44 ].\nThe oncogenic potential of LncRNA GIHCG has been documented. It has been observed to exhibit upregulation and facilitate cellular proliferation and migration across various tumour types [ 45 ].  LncRNA GIHCG  exhibited a gradual increase throughout the development of hepatocarcinogenesis and demonstrated a higher expression in HCC tissues when compared to adjacent non‐tumour tissues. Moreover, there is a significant association between elevated levels of  GIHCG  and larger tumour size, microvascular invasion, advanced Barcelona Clinic Liver Cancer (BCLC) stage, and unfavourable survival outcomes among HCC patients. Further experimental investigation demonstrated that  GIHCG  induces cellular proliferation and migration of HCC cells in vitro. Furthermore,  GIHCG  enhances xenograft tumour growth and metastatic potential in vivo. Further functional investigation revealed a direct physical interaction between  GIHCG  and  EZH2 , alongside their binding to the promoter regions of  miR‐200b/a/429 . Subsequently, this interaction recruits  EZH2  and  DNMT1  to the  miR‐200b/a/429  promoter sites, increasing histone H3K27 trimethylation and DNA methylation levels. Ultimately, these modifications lead to a significant downregulation of  miR‐200b/a/429  expression. Additionally, the physiological effects of  GIHCG  on HCC are contingent upon  miR‐200b/a/429  suppression. Collectively,  GIHCG/DNMT1/miR 200b/a/429  axis respective functions and operational mechanisms within HCC [ 46 ].\nDDX11‐AS1  on chromosome 12 exhibits oncogenic properties within HCC tissue specimens [ 47 ].  DDX11‐AS1  expression is substantially upregulated in both HCC tissues and cell lines, with elevated  DDX11‐AS1  expression indicating unfavourable overall survival outcomes among patients. Functional analysis revealed that suppressing  DDX11‐AS1  hindered the proliferation, cell cycle advancement and migration of HCC cells, whereas its overexpression yielded contrasting outcomes. Furthermore,  DDX11‐AS1  exerts an inhibitory effect on  LATS2  expression in HCC cells. Significantly,  DDX11‐AS1  interacts with  EZH2  and  DNMT1 , thereby leading to the suppression of  LATS2  expression. Also,  DDX11‐AS1  silencing resulted in elevated levels of both mRNA and protein expression of  LATS2 . Conversely, the  LATS2  upregulation counteracted the stimulatory impact of  DDX11‐AS1  on cellular proliferation and invasion. Besides, in vivo experimentation revealed that  DDX11‐AS1  exerted a facilitative effect on tumour development, while the expression of  LATS2  mRNA displayed a substantial reduction within the tumour tissues and exhibited an inverse association with  DDX11‐AS1  expression. The  DDX11‐AS1/DNMT1/LATS2  pathway could serve as an oncogenic element in hepatocarcinogenesis, presenting a promising avenue for therapeutic intervention in treating HCC [ 48 ].\nLinc‐GALH , otherwise referred to as Gankyrin Associated lincRNA in HCC ( Linc‐GALH ), has been substantiated as an indispensable modulator of HCC.  Linc‐GALH  exhibited a significant level of expression that corresponded closely with the expression of Gankyrin in HCC.  Linc‐GALH  exhibited autonomous and unfavourable prognostic implications for HCC. Functional assays demonstrated that  Linc‐GALH  stimulated the migratory capabilities of HCC cells under in vitro conditions while concurrently augmenting the metastatic potential of HCC cells within the lungs in vivo. Notably,  linc‐GALH  expedites  DNMT1  degradation by augmenting ubiquitination, consequently facilitating the amplification of Gankyrin expression by reducing the methylation status specifically within HCC contexts. In this manner,  linc‐GALH  predominantly facilitates HCC cell migration by upregulating  Gankyrin  expression, achieved primarily via  DNMT1  degradation. Thereby, the  Linc‐GALH/DNMT1/Gankyrin  axis is both a prognostic biomarker and a viable therapeutic target for HCC that warrants investigation [ 49 ].\nGastric cancer (GC) is a prevalent malignancy of the digestive system that exhibits a formidable prognosis, particularly among patients in advanced stages. The annual incidence of GC stands at approximately one million cases. Thus, discernment of innovative biomarkers and an enhanced comprehension of the mechanisms involved in GC carcinogenesis hold significant prominence [ 50 ].\nMiR‐148a  has exhibited tumour‐suppressive properties in the context of GC.  MiR‐148a  exhibited abnormal downregulation in GC tissues and is comparatively lower in the MGC‐803 and HGC‐27 GC cell lines compared to the normal gastric epithelial cell line, GES‐1. Also, a significant association exists between reduced levels of  miR‐148a  and lymph node metastasis and tumour node metastasis (TNM) stage. Notably, overexpression of  miR‐148a  resulted in a notable decrease in the  cells'  in vitro migratory and invasive capabilities. Also,  DNMT1  serves as a direct and functional recipient of  miR‐148a . Moreover,  miR‐148a  inhibitor led to amplified  DNMT1  expression within HGC‐27 cells, while upregulation of  miR‐148a  resulted in reduced  DNMT1  expression in MGC‐803 cells. Furthermore, overexpression of  DNMT1  effectively counteracted the suppressive effects exerted by  miR‐148a  on cellular migration. Taken together,  miR‐148a  exerts inhibitory effects on cellular migration in GC by modulating  DNMT1  activity [ 51 ]. Furthermore,  miR‐148a  could also function in GC pathogenesis via  MEG3 .  MEG3  is upregulated following the silencing of D N MT1 in GC cells. Additionally, inhibiting  MEG3  reduces the inhibitory effect on cell proliferation caused by the upregulation of  miR‐148a . Notably, the inhibitory effect on  miR‐148a  might play a role in the decreased expression of  MEG3  in GC through the regulation of  DNMT1 . In this manner, the  miR‐148a/DNMT1/MEG3  axis exhibits promising potential as a therapeutic target for the treatment of GC [ 52 ]. In addition, Zuo et al. explored the involvement of miR‐148a and DNMTs in  RUNX3  promoter methylation and its subsequent impact on gene expression. It was observed that the expression of  RUNX3  mRNA exhibited a notable decrease in GC tissues as opposed to the corresponding normal tissues. Furthermore, this downregulation displayed a strong correlation with the expression of  miR‐148a . A notable upregulation in the levels of  RUNX3  mRNA/protein and the unmethylated state of the  RUNX3  promoter was discerned after the administration of the DNA methylation inhibitor 5‐aza‐2′‐deoxycytidineto human GC AGS and BGC‐823 cells, as compared to cells that were not subjected to treatment. They additionally observed that the  miR‐148a  upregulation, a microRNA known to regulate  DNMT1  and  DNMT3B , resulted in elevated levels of  RUNX3  expression within GC cells. They subsequently revealed that  DNMT1  silencing elevated  RUNX3  mRNA/protein levels, whereas  DNMT3B  silencing exhibited no discernible impact on these parameters within BGC‐823 cells. They also demonstrate the potential influence of  miR‐148a  on the regulation of  RUNX3  gene expression in GC, whereby it appears to modulate  DNMT1 ‐mediated DNA methylation. These results shed light on a novel mechanism of gene expression regulation involving the interplay between microRNAs and epigenetic modification [ 53 ]. Importantly, Zhu et al. provided evidence indicating a consistent decrease in  miR‐148a  expression and heightened promoter region methylation in both GC tissues and cell lines. Inhibiting  DNMT1  expression reduced the methylation level of the  miR‐148a  promoter and subsequently facilitated the restoration of its expression. Also, excessive expression of  miR‐148a  in cancer cell lines led to a decline in  DNMT1  expression and hindered cell proliferation without any noticeable alteration in apoptosis rates. Moreover, DNA hypermethylation of the promoter region plays a role in the inactivation of  miR‐148a  in GC. Further, diminished expression of  miR‐148a  attenuates its inhibitory effect on  DNMT1  in GC, potentially leading to upregulated levels of  DNMT1  and facilitating DNA hypermethylation. Thereby, the  miR‐148a/DNMT1  axis is critically involved in the development of GC [ 54 ].\nmiR‐30b , an endogenous miRNA derived from the gene on chromosome 8q24.22, exerts suppressive functions on cell proliferation and epithelial‐mesenchymal transitions (EMT) in various cancerous conditions [ 55 ].  MiR‐30b‐5p  is significantly downregulated in GC specimens and associated with lymph node metastasis.  MiR‐30b‐5p  levels could be restored through DNA demethylation, while  DNMT1  induced  miR‐30b‐5p  promoter methylation. Further, functional experimentation suggested that the enforced expression of  miR‐30b‐5p  impacted cell migration, aligning with the tissue analysis findings. These discoveries offer an initial understanding of the epigenetic process underlying the downregulation of  miR‐30b‐5p , facilitated by  DNMT1 . They shed light on the functional involvement of  miR‐30b‐5p  in the development of GC [ 56 ].\nThe chromosomal locus of miR‐185 is on chromosome 22, and it exerts tumour‐suppressive effects by modulating numerous pivotal biological processes including autophagy, apoptosis, EMT and the cell cycle of cancer cells [ 57 ]. Recent investigation disclosed that  GKN1  restitution exerted a suppressive effect on the proliferation of GC cells by instigating the production of endogenous miR‐185, which explicitly targets epigenetic regulators  DNMT1  and  EZH2  within the GC cells.  GKN1  ectopic expression resulted in  Tip60  overexpression and the  HDAC1  reduction in a  miR‐185 ‐independent manner within GC cells. Consequently, this led to cell‐cycle arrest by modulating the expression of cell‐cycle proteins. Furthermore, an inverse relationship exists between the expression of  GKN1  and that of  DNMT1  and  EZH2  in a specific subgroup of GC. Interestingly,  GKN1  demonstrated a synergistic anti‐cancer effect when combined with 5‐fluorouracil in inhibiting tumour cell proliferation, thus implying a potential therapeutic approach for addressing GC. Therefore, the  GKN1/miR‐185/DNMT1  axis suppresses gastric carcinogenesis by controlling epigenetic modifications and cell cycle regulation [ 58 ].\nThe lncRNA HOX transcript antisense RNA ( HOTAIR ) gene is located on chromosome 12q13.13. Extensive investigations have consistently demonstrated significant overexpression of  HOTAIR  in diverse types of human malignancies [ 59 ].  HOTAIR  is upregulated, whereas  PCDH10  is reduced in GC. Depletion of  HOTAIR  resulted in a substantial increase in the mRNA/protein levels of  PCDH10  while concurrently reducing  PCDH10  methylation. Furthermore,  DNMT  expression substantially decreased upon  HOTAIR  silencing, while  HOTAIR  overexpression increased  DNMT1  expression. Further mechanistic analysis demonstrated an interaction between  miR‐148b  and  HOTAIR . Moreover,  HOTAIR  silencing triggered  miR‐148b  overexpression, whereas the overexpression of  miR‐148b  had a corresponding downregulatory effect on  HOTAIR  expression. Furthermore,  HOTAIR  silencing and the introduction of  miR‐148b  mimic resulted in diminished  DNMT1  expression and  PCDH10  upregulation in GC. In this manner,  HOTAIR  interacts with  miR‐148b  and  DNMT1 , ultimately resulting in the methylation of  PCDH10 , thereby playing a role in the advancement of GC [ 60 ].\nSmall nucleolar RNA host gene 1 ( SNHG1 ), situated on 11q12.3, is pivotal in the progression and prognostication of numerous cancer types [ 61 ].  LncRNA‐SNHG1  expression is markedly elevated within GC tissues compared to adjacent tissues, positively associated with various clinicopathological parameters, including lymph node metastasis, T stage and TNM stage. So, patients with elevated levels of  lncRNA‐SNHG1  expression exhibited markedly reduced survival times compared to those with lower levels of expression. Further,  lncRNA‐SNHG1  significantly facilitated the proliferation of GC cells and enhanced DNMT1 expression. Therefore,  lncRNA SNHG1  enhances the expression of  DNMT1 , thereby fostering the process of GC cell proliferation [ 62 ].\nLncRNA SAMD12‐AS1  is derived from the antisense strand of the  SAMD12  gene, which is situated on human chromosome 8. It demonstrates dual roles as both a tumour suppressor and an oncogene [ 63 ].  SAMD12‐AS1  exhibited substantial overexpression in both human GC tissues and cell lines compared to their normal counterparts. Elevated levels of  SAMD12‐AS1  expression are significantly associated with advanced TNM stage and reduced survival duration in individuals diagnosed with GC.  SAMD12‐AS1  augments the oncogenic potential of GC cells by impeding the P53 signalling pathway. Further functional examination revealed that  SAMD12‐AS1  potentially executes its biological functions in GC through direct interaction with  DNMT1 , thereby enhancing  DNMT1 ‐mediated repression of the P53 signalling pathway. In this manner,  SAMD12‐AS1  contributes to the advancement of GC through the  DNMT1/P53  pathway [ 64 ].\nColorectal cancer (CRC), a prevalent neoplasm, ranks as the third leading contributor to mortality associated with cancer for both genders. Consequently, a comprehensive comprehension of the molecular mechanisms and pathways that drive CRC advancement is imperative, as it holds the potential for advancing innovative diagnostic techniques and targeted therapeutic interventions [ 65 ].\nMiR‐515–5p  is initially characterised as a miRNA specific to the placenta, playing a role in foetal development and growth. Several experimental studies have proposed that  miR‐515‐5p  exhibits tumour‐suppressive properties across different human cancers [ 66 ].  Circ_0040809  and  DNMT1  expression are significantly upregulated, while  miR‐515‐5p  expression is downregulated in both CRC tissues and cells. Elevated levels of  circ_0040809  expression significantly correlate with decreased overall survival. Further experimentation disclosed that the suppression of  circ_0040809  impedes the proliferation and migration of CRC cells and encourages apoptosis. Conversely, the upregulation of  circ_0040809  yields contrasting effects. A mechanistic examination revealed that  circ_0040809  engages in competitive binding with  miR‐515‐5p , resulting in an upregulation of  DNMT1  expression. Notably, partial attenuation of the tumour‐promoting effects mediated by  circ_0040809  can be observed through the overexpression of  miR‐515‐5p . Thereby,  circ_0040809  enhances CRC cells' proliferative and migratory capabilities while impeding apoptosis by exerting regulatory control over the  miR‐515‐5p/DNMT1  pathway [ 67 ].\nWang et al. explored the impact of  DNMT1  on the biological properties of CRC cells. Their investigation revealed the presence of increased levels of  DNMT1  and  TMSB10  expression, diminished  miR‐152‐3p  expression and methylated  miR‐152‐3p  in both CRC tissues and cells. They observed that the downregulation of  DNMT1  or the upregulation of  miR‐152‐3p  resulted in a decrease in  TMSB10  expression, thereby exerting inhibitory effects on the progression of CRC and the growth of tumours. They additionally revealed that an increased expression of  DNMT1  could counteract the impact of  miR‐152‐3p  upregulation on the progression of CRC and the growth of tumours. They ultimately disclosed that  DNMT1  played a role in preserving the methylation pattern of  miR‐152‐3p , and  miR‐152 , in turn, directly targets  TMSB10 . Thereby, inhibition of  DNMT1  leads to the absence of methylation in  miR‐152‐3p , causing a reduction in  TMSB10  expression and subsequently impeding CRC progression [ 68 ].\nRecent in silico analysis detects promoter region methylation of  CNN1  in CRC. In vitro investigations revealed hypermethylation of the  CNN1  promoter region, specifically in the context of CRC, which is associated with reduced  CNN1  expression in both CRC tissues and cells. Further mechanistic investigation provided compelling evidence that  LINC00337  facilitated the recruitment of  DNMT1  to the promoter region of  CNN1 , thereby exerting transcriptional repression on  CNN1 . These findings demonstrate that hypermethylation of the  CNN1  promoter region in CRC is associated with increased expression of  LINC0033 . Further functional analyses showed that the upregulation of  CNN1  or  LINC00337  silencing impeded CRC cell proliferation, migration/invasion and proangiogenetic activity in vitro. These findings were further supported by in vivo experiments, which demonstrated enhanced tumour growth, increased MVD and increased levels of  VEGF  and  Ki67 .  LINC00337  promotes the development of tumours and angiogenesis in CRC by recruiting  DNMT1  to suppress  CNN1  [ 69 ].\nPancreatic cancer represents a highly malignant neoplasm of the digestive system, displaying a poor prognosis. The majority of individuals who have pancreatic cancer receive their diagnosis during advanced stages or even when metastasis has occurred, owing to its remarkably aggressive nature and absence of discernible early symptoms. Thus, timely detection of pancreatic cancer plays a pivotal role in enhancing its prognosis [ 70 ].\nmiR‐34a , belonging to the  miR‐34  family, is situated on chromosome 1p36. It is recognised as a pivotal controller of tumour suppression. Consequently, trials have been undertaken to explore the clinical use of miR‐34a replacement, marking it as the initial endeavour in utilising miRNA for cancer therapy [ 71 ]. According to recent experimentation in pancreatic cancer,  DNMT1  exerts repressive effects on  miR‐34a  expression while concurrently promoting the activation of the Notch pathway through mediation of the hypermethylation process targeting the  miR‐34a  promoter region. An inverse correlation is observed between the expression levels of  DNMT1  and  miR‐34a  in individuals diagnosed with pancreatic cancer. Mechanistically,  DNMT1  silencing reduced methylation levels at the promoter region of  miR‐34a , leading to an upregulation of  miR‐34a  expression. Consequently, this upregulation exerted inhibitory effects on the Notch pathway activity. Furthermore, attenuation of the Notch signalling pathway through the  DNMT1 / miR‐34a  axis substantially augmented the susceptibility of pancreatic cells towards molecular targeting agents. Thereby, downregulation of DNMT exhibits a stimulatory effect on the expression of  miR‐34a , highlighting its prospective utility as a therapeutic target for pancreatic cancer [ 72 ].\nIn pancreatic cancer, increased expression of  DNMT1  and aberrant methylation of promoters implicated in the downregulation of  KLF4  expression result in impaired differentiation and unfavourable outcomes. Also, modulation of  KLF4  expression substantially impacts the expressions of differentiation markers in cells afflicted with pancreatic cancer. In addition, administration of 3, 3′‐diindolylmethane (DIM) through the diet substantially stimulates the expression of  miR‐152 . Consequently, this upregulation hinders the expression of  DNMT1  protein and its interaction with the promoter region of  KLF4 , resulting in a decrease in promoter DNA methylation and the activation of  KLF4  expression within pancreatic cancer cells. Notably, administration of DIM results in notable suppression of cellular proliferation in vitro and the inhibition of tumour formation in animal models of pancreatic cancer. In this manner, induction of the  miR‐152/DNMT1/KLF4  signalling pathway through epigenetic mechanisms by dietary DIM leads to the differentiation and substantial growth suppression of pancreatic cancer cells. This finding underscores its potential translational relevance for pancreatic cancer and other malignancies [ 73 ].\nAccording to recent experiments, there is mutual influence between  miR‐148a  and  DNMT1 , which could impact cellular proliferation and migration in pancreatic cancer cells. Accordingly, restoration of miR‐148a resulted in the reactivation of TSGs, including  p16 ,  preproenkephalin  and  Ras association domain family member 1  in the AsPC‐1 pancreatic cancer cell line by specifically targeting  DNMT1 . Importantly, upregulation of  miR‐148a  significantly inhibits cell proliferation and migration in AsPC‐1 cells. Thereby, targeting  miR‐148a/DNMT1  could be a promising therapeutic strategy for managing pancreatic cancer [ 74 ].  p27  is another gene in which miR‐148a could suppress pancreatic cancer advancement. In this regard, it was disclosed that overexpression of miR‐148a by suppressing DNMT1 hindered the methylation process of  p27 , resulting in an elevated expression of  p27 . This is associated with attenuated proliferative and metastatic capacities of ASPC‐1 cells. Interestingly, the suppression of  DNMT1  resulted in  miR‐148a  upregulation. Notably, in vivo investigations provided substantial evidence for effectively suppressing ASPC‐1 tumorigenesis through upregulating  miR‐148a  or  DNMT1  silencing [ 75 ]. Furthermore,  miR‐148b  and‐152, by regulating the expression of  SPARC  and  BNIP3 , play a crucial role in pancreatic cancer pathogenesis. It was disclosed that upregulation of  miR‐148b  and‐ 152  led to the restoration of DNA methylation patterns to their normal states and facilitated TSGs re‐expression, such as  SPARC  and  BNIP3  in pancreatic cancer cell lines (AsPC‐1 and MIA PaCa‐2). In summary, miRs that specifically target  DNMT1  and modulate the methylation patterns of TSGs like  BNIP3  and  SPARC  can potentially be utilised as a therapeutic approach for inducing apoptosis in pancreatic cancer cells and reducing their tumorigenic properties [ 76 ].\nMiR‐377 , an RNA molecule synthesised by the 14q32 miRNA cluster, has been identified as a key contributor to the pathogenesis of diverse malignancies, including pancreatic cancer [ 77 ]. A reciprocal relationship exists between  miR‐377  and  DNMT1  in pancreatic cancer cells, where  DNMT1 ‐mediated promoter methylation significantly influences miR‐377 expression, while  DNMT1  itself functions as a downstream target of  miR‐377 . In tumour specimens, a discernible presence of hypermethylation in the promoters of  PENK ,  TFPI2 ,  SPARC  and  BNIP3  was observed, whereas normal tissues exhibited no such methylation patterns. Notably,  miR ‐ 377  exhibited substantial suppressive effects on cellular proliferation while triggering apoptosis. Therefore, in pancreatic cancer cells, the modulation of  miR‐377 , specifically by targeting  DNMT1 , can potentially diminish DNA methylation levels associated with specific TSGs, thereby facilitating the reinstatement of their expression [ 78 ].\nHaematological malignancies encompass malignant neoplasms arising from the aberrant differentiation of haematopoietic stem cells (HSCs). Researchers are compelled to explore innovative treatment targets and mechanisms due to the prevalent systemic engagement, unfavourable prognosis, chemoresistance and frequent recurrence observed in haematological malignancies [ 79 ].\nIn acute myeloid leukaemia (AML) patients,  miR‐148a  expression was significantly downregulated, while DNMT1 was upregulated. The methylation status of the  miR‐148  promoter markedly increased in AML cell lines, highlighting the underlying cause for the decreased expression of  miR‐148a  in both AML patients and cell lines. In contrast, silencing  DNMT1  significantly reduces the methylation level of the  miR‐148a  promoter, resulting in a substantial upregulation of  miR‐148a  expression. Subsequent experimentation demonstrated that  miR‐148a  exerts direct negative regulatory control over  DNMT1 , and overexpression of  miR‐148a  decreased expression levels of  DNMT1  in terms of mRNA/protein. Conversely, silencing  miR‐148a  in Kasumi‐1 cells led to an elevation in  DNMT1  expression levels. Further cellular analysis showed that elevated expression of  miR‐148a  suppressed cellular proliferation while simultaneously fostering apoptosis. In this manner, these findings indicate the existence of a reciprocal negative feedback loop between  miR‐148a  and  DNMT1  in the context of AML [ 80 ].\nSilencing  DNMT1  significantly increases the expression of TSGs ( SHP‐1, p14, p16, BCL2L10  and  SOCS3 ) by reducing their methylation levels in OCI‐Ly10 and Granta‐159 cells. At the cellular level, suppression of  DNMT1  hinders the cellular proliferation, formation of cell colonies and progression of the cell cycle while also triggering apoptosis in lymphoma cells. Furthermore,  miR‐152  exerts its downregulatory effect on  DNMT1  expression by directly targeting the gene, and  miR‐152  overexpression results in elevated expression levels of TSGs, specifically  SHP‐1  and  SOCS3 . Additionally,  miR‐152  induces apoptosis and impedes cell proliferation. Moreover, the upregulation of  miR‐152  has a profound inhibitory effect on tumour development in vivo, as evidenced by a reduction in  DNMT1  expression and an augmentation in the expression of TSGs. In this manner,  miR‐152  exerts an inhibitory effect on lymphoma growth through its capacity to suppress the  DNMT1 ‐mediated silencing mechanism of  SOCS3  and  SHP‐1  [ 81 ].\nRecent exploration disclosed that the expressions of  HOTAIR  and  DNMT1  elevated, whereas  PTEN  demonstrated decreased expression in both CML cells and the bone marrow of CML patients.  HOTAIR  predominantly engaged in molecular interactions with  DNMT1 , while  DNMT1  primarily exhibited binding affinity towards the promoter region of  PTEN . So,  HOTAIR , by binding with  DNMT1 , modulates  PTEN  promoter methylation. Additionally, depletion of  HOTAIR  or  DNMT1  resulted in diminished migration, colony formation, proliferation and increased apoptosis rate of CML cells. Furthermore, reduced expression of  HOTAIR  and  DNMT1  led to decreased tumour volume and weight in mice injected with CML cells. Thereby, a reduction in  HOTAIR  levels inhibits its association with  DNMT1 , consequently impeding the growth of CML cells and promoting programmed cell death. This phenomenon is intricately linked to the control of  PTEN  promoter methylation [ 82 ].\nDysregulation of  LINC00173 , an intergenic noncoding RNA positioned at chromosome 12q24.22, has been highlighted in various human cancer types [ 83 ].  LINC00173  displays decreased expression levels, while  DNMT1  increases in AML. Additionally, they discovered a negative correlation exists between the methylation of the  LINC00173  promoter and its expression. These findings were consistent across multiple databases, including GEPIA and CCLE and in various contexts, such as benzene‐exposed workers, B‐cell non‐Hodgkin's lymphoma and HQ‐induced malignantly transformed TK6 cells (HQ‐MT cells). Mechanistic investigation disclosed that depletion of  DNMT1  led to diminished  LINC00173  promoter methylation in HQ‐MT cells. Furthermore,  LINC00173  upregulation suppressed  DNMT1  expression while inhibiting cell proliferation and tumour growth in HQ‐MT cells. Additionally, this overexpression increased responsiveness to cisplatin chemotherapy and promoted apoptosis. Notably, an interaction between  LINC00173  and  DNMT1  takes place to exert control over the methylation process of the LINC00173 promoter region. Overall, the interplay between  DNMT1  and  LINC00173  governs the modulation of  LINC00173  expression via regulation of its promoter methylation level. This, in turn, modulates the functioning of HQ‐MT cells both in vitro and in vivo, thereby presenting a novel therapeutic target for benzene‐induced tumours [ 84 ].\nOvarian cancer (OC) is an exceptionally aggressive malignancy that significantly endangers the well‐being of women and presents formidable obstacles for healthcare practitioners. On a global scale, this malignancy ranks as the seventh most prevalent form of cancer and the eighth primary contributor to mortality among women who have cancer. Thus, the global health burden of OC necessitates immediate attention to molecular investigations that offer novel approaches to enhancing disease prognosis [ 85 ].\nGeng and colleagues explored the contribution of  DNMT1  in the pathophysiology of polycystic ovary syndrome (PCOS). They noted a significant upregulation of  lnc‐MAP3K13–7:1  in granulosa cells (GCs) from individuals diagnosed with PCOS. This was accompanied by a concurrent decrease in global DNA methylation levels, reduced expression of  DNMT1  and elevated levels of  cyclin‐dependent kinase inhibitor 1A  ( CDKN1A ,  p21 ) expression. They observed that the upregulation of  lnc‐MAP3K13–7:1  in KGN cells led to a halt in cell cycle progression, specifically in the G0/G1 phase. Additionally, it resulted in the suppression of  DNMT1  at the molecular level. Their mechanistic investigation unveiled that  lnc‐MAP3K13–7:1 , through its role as a protein‐binding scaffold, effectively suppressed the expression of  DNMT1  and led to ubiquitin‐mediated degradation of the DNMT1 protein.  DNMT1 ‐dependent  CDKN1A  promoter hypomethylation also increased  CDKN1A  transcription, inhibiting GC growth. In this manner,  lnc‐MAP3K13–7:1 ‐dependent inhibition of  DNMT1  controls the expression of  CDKN1A / p21  and impedes the proliferation of GC cells [ 86 ].\nBreast cancer is the prevailing malignancy among women, and despite therapeutic advancements, it remains the primary contributor to cancer‐related mortality in females on a global scale. The limited range of therapeutic interventions for BC can be attributed to the prevalent manifestation of chemoresistance. Consequently, there is a need to unravel the fundamental molecular mechanisms underlying this pathology and advance novel approaches to managing this disease [ 87 ].\nmiR‐497 , an extensively preserved microRNA transcribed from the initial intron of the  MIR497HG  (Gene ID: 100506755) gene situated on the 17p13.1 locus of the human chromosome, is a member of the miR‐15 family.  MiR‐497  reduction has been evident in diverse carcinoma types, such as BC, thereby implying the potential tumour‐suppressive function of miR‐497 [ 88 ]. The  miR‐497/GPRC5A  axis, a recently identified mediator of BC, could be regulated through  DNMT1 . In the context of  BC ,  DNMT1  is significantly increased, while the expression of  GPRC5A  is reduced. Overexpression of  DNMT1  significantly enhances both resistance to chemotherapy and the metastatic potential of BC.  DNMT1  induces modifications in the methylation status of the CpG island located within the promoter region of  miR‐497 , consequently repressing  miR‐497  expression. Notably,  miR‐497  exhibited a specific affinity for inhibiting  GPRC5A  expression, thereby impeding chemotherapy resistance and suppressing the metastatic potential of BC cells. In this manner,  DNMT1  potentially obstructs  miR‐497  and enhances the activation of  GPRC5A  via methylation, thereby intensifying the resistance to chemotherapy and metastasis in BC [ 89 ].\nSengupta et al. explored the interrelationship between  miR‐152 ,  DNMT1  and  CDH1  activity concerning BC's metastatic potential and aggressiveness. They noticed that  miR‐152  directly regulates  DNMT1  in the MDA‐MB‐231 cell line. They confirmed a correlation between elevated expression of  DNMT1  and gene hypermethylation, which subsequently triggers  miR‐152  gene repression. They subsequently unveiled the pivotal involvement of  DNMT1  in governing the regulatory mechanisms of the  miR‐152  gene. They noticed that inhibition of  DNMT1  protein activity leads to the dominance of  miR‐152  expression, resulting in the degradation of  DNMT1  mRNA. This intricate regulatory mechanism forms a recurring feedback loop, currently being investigated as the  DNMT1/miR‐152  switch for controlling the activation and deactivation of target genes regulated by  DNMT1 . Their investigation yielded the identification of a regulatory mechanism wherein the  DNMT1/miR‐152  switch exerts influence over the modulation of  CDH1  gene expression. In addition, silencing  DNMT1 , which leads to the upregulation of  CDH1 , also known as the  DNMT1/CDH1  loop, in the presence of excessive ectopic expression of  miR‐152  effectively inhibits the migratory capability of cancer cells. Thus, the interplay of  miR‐152 ,  DNMT1  and  CDH1  signifies a pivotal involvement in BC metastasis [ 90 ]. In addition, Xu et al. observed that  miR‐148a  and  miR‐152  expression levels exhibit a reduction in BC tissues and cells owing to CpG island hypermethylation. Next, they observed an abnormal increase in the expression of  DNMT1  in BC, and this heightened expression is the primary cause of excessive methylation observed in the promoters of  miR‐148a  and  miR‐152 . Intriguingly, an inverse correlation exists between the expression levels of  miR‐148a/152  and  DNMT1 , a target gene impacted by  miR‐148a/152 . Their outcomes led them to put forward a hypothesis suggesting the existence of a negative feedback regulatory loop between  miR‐148a/152  and  DNMT1  in the context of BC. More importantly, they disclosed that  miR‐148a  and  miR‐152  effectively target the proteins  IGF ‐IR and  IRS1 , which are frequently upregulated in BC. The overexpression of either  miR‐148a  or  miR‐152  significantly inhibits BC tumour angiogenesis, colony formation and cell proliferation. This inhibitory effect is achieved by targeting  IGF‐IR  and  IRS1 , suppressing the downstream signalling pathways of AKT and MAPK/ERK. In this manner, their findings propose an innovative regulatory pathway involving  miR‐148a/152  and  DNMT1 , highlighting the tumour suppressive roles of  miR‐148a  and  miR‐152  by targeting  IGF‐IR  and  IRS1  [ 91 ].\nmiR‐185  significantly decreased within both triple‐negative breast cancer (TNBC) tissues and cell lines and correlated with various clinical factors, including overall survival, clinical stage, lymph node metastasis and relapse‐free survival in TNBC. Additionally, aberrant  miR‐185  ectopic expression suppressed TNBC cell proliferation both in vivo and in vitro. Furthermore,  miR‐185  exhibited direct binding specificity towards  DNMT1  and  E2F6 , leading to a substantial upregulation of  BRCA1  expression at both the mRNA and protein levels in TNBC. Therefore,  miR‐185  plays a role in inhibiting tumour growth during the development of TNBC, suggesting the  miR‐185/DNMT1  axis is a promising therapeutic approach for TNBC [ 92 ].\nThe  miR‐142  gene at the chromosomal locus 17q22 plays a significant role in modulating cellular migration, proliferation and apoptotic processes across various malignancies [ 93 ]. Myocardin‐related transcription factor A ( MKL ‐1) can adhere to the conserved cis‐regulatory element CC (A/T) 6GG, commonly referred to as the CarG box, situated within the  miR‐142‐5p  promoter region. This interaction facilitates the regulation of  miR‐142‐5p  transcription. Furthermore, experimental evidence demonstrated that  miR‐142‐5p  directly targets the 3′‐UTR region of  DNMT1 , suppressing  DNMT1  expression. As a result, a feedback loop is established, hindering BC cell migration and proliferation. So, their study offers significant and innovative contributions to understanding the  MKL‐1/miR‐142‐5p/DNMT1/maspin  signalling pathway, potentially serving as a novel concept for BC's diagnosis, treatment and prognosis [ 94 ].\nLncRNA H19 , an early‐identified lncRNA, is situated within the genomic vicinity of chromosome 11p15.5. The aberrant upregulation of  H19  is widely believed to be implicated in the oncogenesis and advancement of various cancers across different anatomical systems in the human body, including the breast [ 95 ].  H19  significantly upregulated in both human breast tumour tissues and cells. H19 displays an inverse association with the expression levels of  miR‐152 , while a direct relationship exists between the expression levels of  H19  and  DNMT1  mRNA. Mechanistically,  H19  functions as an endogenous sponge by directly associating with  miR‐152 , while  miR‐152  specifically regulates  DNMT1 . So, the upregulation of  H19  significantly alleviated the inhibitory effects of  miR‐152  on the expression of  DNMT1 . Furthermore, the pronounced antagonistic impacts of  H19  downregulation on cellular proliferation and invasion are effectively counteracted by the inhibition  miR‐152  and the enhanced expression of  DNMT1 . In conclusion,  H19  facilitated the proliferation and invasion of BC via the  miR‐152/DNMT1  axis, presenting a novel explanatory mechanism elucidating the pathogenesis and progression of BC [ 96 ].\nEC is categorised as a gynecologic malignancy and ranks as the sixth most prevalent tumour among females. The present therapeutic strategies for EC encompass chemotherapy, radiotherapy, brachytherapy and surgical excision. Despite significant advancements in the therapeutic domain concerning EC within the last few years, the prognosis for EC remains unfavourable. Consequently, it is imperative to delve into the molecular mechanisms that facilitate the advancement of EC to enhance the efficacy of its treatment [ 97 ].\nmiR‐148b ‐mediated regulation of  DNMT1  has been identified as a key factor in the pathogenesis of EC. In this context, the expression of  miR‐148b  greatly decreased in both EC tissues and HEC‐1A and HEC‐1B cells, while  DNMT1  exhibited elevated expression levels. Overexpression of  miR‐148b  resulted in the suppression of cellular proliferation and hindered the progression of the cell cycle while concurrently promoting cellular apoptosis. In EC cells, it was ascertained that  DNMT1  functions as a target gene of  miR‐148b . Thereby,  miR‐148b  exerts an inhibitory effect on cellular proliferation and promotes apoptotic processes in EC by modulating the activity of  DNMT1  [ 98 ]. Additionally,  miR‐148b  plays a crucial role in hypoxic stress‐mediated epigenetic modifications in the pathogenesis of EC. In this vein,  DNMT1  protein expression decreased within ectopic endometriotic stromal cells compared to eutopic endometrial stromal cells, and exposure to hypoxia resulted in a substantial downregulation of  DNMT1  levels. Also, there is a direct targeting of  DNMT1  by  miR‐148a , establishing evidence for the hypothesis that the decreased expression of  DNMT1  in ectopic endometriotic stromal cells could be attributed to elevated levels of  miR‐148a . Furthermore, hypoxia diminishes the presence of HuR protein and its interaction with the AU‐rich element (ARE) situated at the 3′‐UTR of  DNMT1  transcript, consequently resulting in the heightened affinity of AUF1 to the aforementioned ARE. This observation substantiates the hypothesis positing competitive engagement between AUF1 and HuR. Additionally, AUF1 binding to the ARE facilitates recruitment of the  miR‐148a ‐AGO2 complex to the adjacent  miR‐148a  binding site, thereby shedding light on the mechanism by which AUF1 binding leads to diminished mRNA stability. The researchers' discovery is substantiated by a recent report indicating that AUF1 assists in recruiting miRNA‐loaded AGO2 to specific mRNA targets. Accordingly, these findings illustrate the influence of the interplay between AUF1 and HuR on the effectiveness of miR‐148a targeting. Consequently, this intricate relationship is significant in governing the regulation of  DNMT1  expression and DNA methylation in response to hypoxic stress conditions. Therefore, microenvironmental hypoxia plays a vital role in suppressing  DNMT1  through the involvement of  AUF1 / miR‐148a . Consequently, the downregulation of  DNMT1  leads to epigenetic modifications. Therefore, manipulating the interactions among  AUF1 ,  miR‐148a  and the transcript of  DNMT1  holds potential for future development in restoring  DNMT1  expression [ 99 ].\nProstate cancer (PCa) is a complex condition that arises from various causal factors, encompassing epigenetic modifications and genomic changes. Although the conventional diagnostic criterion for PCa involves assessing the prostate‐specific antigen (PSA) in the bloodstream, it is noteworthy that this biomarker may also exhibit elevated levels in other prostate‐related ailments, such as prostatitis and benign prostatic hyperplasia. Moreover, no apparent correlation exists between the PSA level and the PCa stage. To effectively manage PCa in a clinical setting, it is imperative to identify novel and dependable biomarkers that offer therapeutic, prognostic and diagnostic insights [ 100 ].\nDNMT1  is a significant driver of  miR‐148a ‐mediated biological processes in the pathogenesis of PCa. In this context, in silico analysis of miRNA target prediction indicated that  miR‐148a  exhibits a binding affinity towards the 3′ UTR of  DNMT1  mRNA, potentially inducing  DNMT1  gene silencing. Furthermore,  miR‐148a  ectopic expression triggers apoptosis and impedes cellular proliferation by suppressing  DNMT1 . Moreover, a regulatory relationship exists between DNA methylation,  DNMT1 , and the  miR‐148a  gene in the context of PCa. So, DNA methylation plays a role in the suppression of miR‐148a. In contrast, overexpression of  miR‐148a  leads to the downregulation of  DNMT1  expression and the activation of apoptotic genes in hormone‐refractory prostate cancer cells [ 101 ]. In addition,  DNMT1  could also exert its effects on PCa pathogenesis through the regulation of  miR‐152 . In this regard,  miR‐152  exhibits significant differential expression in prostate cancer cell lines AA and CA and is markedly downregulated in the more aggressive cells. However, 5‐aza‐2′‐deoxycytidine an inhibitor of  DNMT1 , significantly reduced the methylation status of the  miR‐152  promoter, resulting in increased expression of  miR‐152 . Furthermore, they observed that the overexpression of  miR‐152  led to a notable reduction in cellular growth and migration, while downregulation of  miR‐152  exerts opposite effects. Further exploration demonstrated that  miR‐152  directly targets  DNMT1 , and ectopic expression of  miR‐152  leads to the downregulation of  DNMT1 . This finding suggests a reciprocal regulatory association between the expression of  miR‐152  and  DNMT1 . Thereby, modulation of  miR‐152/DNMT1  through epigenetic mechanisms significantly influences various processes associated with the malignant behaviour of PCa tumours, particularly in AA PCa patients [ 102 ].\nGlioma, a prevalent malignant neoplasm originating from neuroepithelial tissue within the central nervous system, constitutes 40% to 50% of intracranial tumours. This disease exhibits a poor prognosis and elevated mortality rates. Consequently, the clinical management of glioma necessitates the identification of novel biomarkers for diagnosis, prognosis and therapeutic intervention [ 103 ].\nmiR‐148‐3p  is primarily involved in glioblastoma multiforme (GBM) through its direct regulatory effects on  DNMT1  and recombinant human runt‐related transcription factor 3 ( RUNX3 ).  MiR‐148‐3p  is significantly reduced in glioma tissues compared to adjacent nontumor tissues and correlated with various factors, including WHO grade, tumour size, prognosis, as well as  DNMT1  and  RUNX3  expressions. This decrease coincided with a  DNMT1  upregulation and  RUNX3  promoter region hypermethylation. Further cellular analysis revealed that the upregulation of  miR‐148‐3p  resulted in apoptosis and cell cycle arrest in U251 and U87 and influenced cell migration. Additionally, overexpression of  miR‐148‐3p  inhibited  DNMT1  expression and  RUNX3  promoter methylation, ultimately leading to  RUNX3  overexpression. Mechanistic analysis discovered a direct interaction between miR‐148‐3p and the 3′‐UTR of  DNMT1 . Subsequently,  miR‐148‐3p  upregulation or  DNMT1  silencing increased  E‐cadherin  expression and decreased  MMP ‐ 9 ,  MMP‐2 ,  N‐cadherin  and  vimentin  expressions. Therefore,  miR‐148‐3p  exhibited direct repression of  DNMT1  expression, inhibiting proliferation and migration in GBM. This regulatory effect is mediated by modulation of the  DNMT1‐RUNX3  axis and the EMT process [ 104 ]. Another mechanistic approach by which  DNMT1  may contribute to glioblastoma pathogenesis is the methylation of the  miR‐152  promoter. In this vein, the  miR‐152  promoter region exhibits hypermethylation, the underlying cause of  miR‐152  downregulation in both glioma tissue samples and cell lines. So,  DNMT1  silencing triggers  miR‐152  upregulation, and there is a negative correlation between  miR‐152  expression and the presence of  DNMT  in glioma cell lines. Also, overexpression of  miR‐152  provoked apoptosis in glioma cells, while  miR‐152  suppression facilitated cell proliferation. Ultimately,  miR‐152  exerts regulatory control over the expression of  Runx2 , and the upregulation of  Runx2  nullified the impacts induced by  miR‐152  upregulation. In this manner, the cellular processes of glioma, specifically cell proliferation and apoptosis, are under the regulatory influence of  miR‐152  in conjunction with  Runx2 , and  DNMT1  is critically involved in  miR‐152  hypermethylation and downregulation [ 105 ].\nNEAT1 , a lincRNA extensively investigated in the domain of cancer pathologies, is synthesised from the multiple endocrine neoplasia (MEN) site located on chromosome 11q13.1 [ 106 ].  NEAT1  mediates the regulation of  DNMT1  expression through its function as a molecular sponge for  miR‐185‐5p .  NEAT1  is significantly upregulated, while  miR‐185‐5p  is downregulated in both glioma tissues and cells. Further in vivo and in vitro investigations substantiated the role of  NEAT1  as a ceRNA in facilitating the expression of  DNMT1  and activating mTOR signalling. Notably,  NEAT1  silencing impeded tumour growth and decreased expression levels of Ki‐67,  DNMT1  and mTOR, whereas it concurrently increased  miR‐185‐5p  expression in an in vivo setting. Moreover,  NEAT1  stimulated glioma activity using modulating mTOR signalling, demonstrated in both in vivo and in vitro settings. In this manner,  NEAT1  functioned as an inhibitory factor on mTOR, thereby facilitating glioma tumorigenesis through the  miR‐185‐5p/DNMT1/mTOR  signalling pathway [ 107 ].\nADAMTS9‐AS2  significantly reduces within tumour tissues compared to normal tissues, with a concomitant inverse correlation between  ADAMTS9‐AS2  expression and tumour grade and prognosis. Elevated levels of  ADAMTS9‐AS2  effectively suppress cell migration in glioma, while  ADAMTS9‐AS2  silencing had the opposite effect. In addition, there is a negative association between the expression of  ADAMTS9‐AS2  and  DNMT1 . Moreover,  DNMT1  silencing resulted in a noteworthy increase in the expression of  ADAMTS9‐AS2 . Therefore,  ADAMTS9‐AS2  functions as a novel tumour suppressor in glioma, and  DNMT1  plays a regulatory role in modulating  ADAMTS9‐AS2  [ 108 ].\nLINC00467 , a long intergenic non‐coding RNA (lincRNAs) with oncogenic properties, exhibits elevated expression in various malignancies, and its increased levels are frequently associated with unfavourable clinicopathological characteristics [ 109 ].  LINC00467  is significantly upregulated in glioma cells compared to normal tissues, and its overexpression enhances proliferative and invasive capabilities and expedites the cell cycle progression in the G0/G1 phase of U87 and LN229 cells. Importantly,  LINC00467  interacts with  DNMT1  and inhibits the expression of  p53 . Furthermore, the upregulation of  p53  counteracts, to some extent, the heightened impact of  LINC00467  on the proliferative and invasive capabilities of glioma cells. Consequently,  LINC00467  overexpression could stimulate glioma cells' proliferative and invasive abilities by inhibiting  p53  expression by binding  DNMT1  [ 110 ].\nThe lncRNA known as maternally expressed gene 3 ( MEG3 ) is within the imprinted DLK1‐MEG3 locus located on the 14q32.3 region of the human chromosome. Its expression frequently decreases in various types of human tumours and cell lines [ 111 ]. Glioma tissues exhibit downregulated expression of  MEG3  due to hypermethylation of its genomic region. In line with previous evidence, administration of 5‐Aza‐2′‐deoxycytidine (5‐AzadC), a DNA methylation inhibitor, resulted in a reduction of abnormal hypermethylation of the  MEG3  promoter and effectively prevented the loss of  MEG3  expression in glioma cells. Therefore, an association exists between  DNMT1  and  MEG3  promoter methylation, wherein  DNMT1  showcased an inverse relationship with  MEG3  expression in gliomas. Additionally,  DNMT1  silencing hindered glioma cells' clone formation and proliferation while concurrently inducing apoptosis. Notably,  DNMT1  silencing contributed to activating  p53  pathways in glioma cells. In this manner, hypermethylation of  MEG3 , facilitated by  DNMT1 , leads to the downregulation of  MEG3  expression and subsequent suppression of p53 signalling pathways in gliomas. Thus, the  MEG3/DNMT1  axis significantly contributes to human glioma pathogenesis, highlighting its potential as a novel therapeutic target in glioma treatment [ 112 ].\nLung cancer, an extensively recognised malignant neoplasm affecting the respiratory system, has inflicted substantial harm upon human well‐being during the 21st century. The mortality and incidence rates in developing and developed countries are influenced by diverse risk factors, the efficacy of diagnostic techniques and/or the availability of treatment options. Hence, to expedite the development of efficacious clinical interventions targeting lung cancer, the potential molecular mechanism of lung cancer development must be further explored [ 113 ].\nIt was discovered that the expression of  miR‐200a  in LUAD cells was significantly reduced and that the direct targeting of 3′‐UTR  GOLM1  resulted in the repression of  GOLM1  expression. Furthermore, when  miR‐200a  was increased, a noticeable inhibition of cell proliferation was observed, effectively impeding the proliferation of LUAD cells induced by  GOLM1  upregulation. It was also discovered that  DNMT1  could downregulate  miR‐200  expression levels, and its excessive expression hindered the suppressive effects of miR‐200a on cellular proliferation. Subsequently,  DNMT1  silencing decreased LAD cell proliferation, which could reverse the introduction of  GOLM1  upregulation. In this manner, the  GOLM1/miR‐200a/DNMT1  axis modulates LUAD cell proliferation [ 114 ].\nLncRNA HAGLR , originating from the HOXD cluster located on the second human chromosome, exhibits increased expression levels across various cancer types [ 115 ].  HAGLR  (also known as HOXD‐AS1) significantly reduces in LUAD tissues.  HAGLR  can diminish LUAD cell proliferation both in vivo and in vitro. Functional investigation disclosed that  HAGLR  exhibits a physical interaction with  DNMT1  and facilitates the recruitment of  DNMT1  on the  E2F1  promoter, thus increasing local DNA methylation. Overall,  HAGLR  facilitated the advancement of LUAD by recruiting  DNMT1  to regulate the methylation patterns and expression of  E2F1  within the promoter region [ 116 ].\nLong non‐coding RNA homeobox A11 antisense ( HOXA11‐AS ) increases, while  miR‐148a‐3p  decreases in NSCLC tissues and cells.  HOXA11 ‐ AS  silencing hindered the proliferation of NSCLC cells and facilitated cellular apoptosis by directly enhancing the expression of  miR‐148a‐3p . Furthermore, upregulation of  miR‐148a‐3p  inhibited NSCLC cell proliferation and induced apoptosis. Additionally,  HOXA11‐AS  acted as a ceRNA for  miR‐148a‐3p , resulting in increased  DNMT1  expression within NSCLC cells. Notably,  DNMT1  overexpression attenuated the impact of  HOXA11‐AS1  depletion on the proliferation and apoptosis of NSCLC cells. In this manner,  HOXA11 ‐ AS  contributes to NSCLC tumourigenesis by modulating the  miR‐148a‐3p/DNMT1  axis [ 117 ].\nOsteosarcoma (OS), a prevalent bone tumour that impacts adolescents and children, necessitates timely identification for successful therapeutic intervention. Hence, there is an imminent need to identify diagnostically and prognostically significant biomarkers, particularly circulating or cellular/tissue biomarkers [ 118 ].\nIn humans,  miRNA‐139 , situated within the genomic locus 11q13.4, exhibits notable antimetastatic and anti‐oncogenic properties [ 119 ].  MiR‐139‐5p  significantly reduces in OS tissues and cell lines. Upregulation of  miR‐139‐5p  effectively inhibits OS growth and migration, while downregulation of miR‐139‐5p induces opposite effects on OS cells.  DNMT1  serves as a specific target of  miR ‐139‐5p. Furthermore, in vivo, findings indicated that the overexpression of  miR‐139‐5p  has a mitigating impact on tumour growth by downregulating the expression of DNMT1. Consequently,  miR‐139‐5p  played a suppressive role in the progression of OS by targeting  DNMT1 , thereby offering novel insights into the underlying molecular mechanism involved in OS development [ 120 ].\nThe expression level of  SNHG7  was significantly elevated in OS tissues compared to adjacent non‐cancerous tissues.  SNHG7  silencing in U2OS and HOS osteosarcoma cell lines led to enhanced cell proliferation, cell cycle arrest at the G0/G1 phase and induction of apoptosis. Mechanistically,  SNHG7  suppressed the transcription of  p53  by forming a complex with  DNMT1 . Subsequently,  p53  upregulation in U2OS cells partially reversed the  SNHG7 ‐mediated enhanced cellular proliferation and apoptosis. In this manner, upregulation of  SNHG7  triggers the proliferation of OS cells while concurrently suppressing apoptosis through the modulation of  p53  expression via direct interaction with  DNMT1  [ 121 ].\nLi et al. explored the role of the  NEAT1/DNMT1  axis in the metastasis of OS. Their findings revealed a substantial upregulation of  NEAT1  expression in both OS tissues and cell lines. Furthermore, they observed a direct association between the  NEAT1  upregulation in OS tissues and unfavourable clinical parameters such as advanced disease stage, poorer prognosis and distant metastasis. Their loss‐ and gain‐of‐function assays disclosed that  NEAT1  positively influenced metastasis in vivo and in vitro. Furthermore, they observed that  NEAT1  ectopic expression led to the induction of EMT. Their mechanistic studies unveiled that  NEAT1  epigenetically silenced  E‐cadherin  expression via its interaction with the  G9a‐DNMT1‐Snail  complex. Their research brings to light a pivotal epigenetic mechanism underlying  NEAT1/DNMT1 ‐mediated metastasis [ 122 ].\nBladder cancer (BCa) represents the second most prevalent urological malignancy. The majority (approximately 75%) of recently identified instances pertain to non‐muscle‐invasive bladder cancer (NMIBC), with the remaining diagnoses attributed to muscle‐invasive bladder cancer (MIBC). Notably, NMIBC patients experience a notable propensity for relapse and advancement. Consequently, an imperative demand exists for dependable prognostic biomarkers to enhance comprehension of disease occurrence and progression [ 123 ].\nLiu et al. indicated a substantial increase in DNMT1 expression in both BCa tissues and cells. Additionally, when  DNMT1  expression was silenced, it resulted in the inhibition of tumour growth in vivo. They unveiled that  miR‐152‐3p  exerted an inhibitory effect on  DNMT1 , and the  DNMT1  upregulation reinstated the cellular functionality of  miR‐152‐3p  in BCa cells. Furthermore,  DNMT1  modulated the expression of  PTEN  by influencing DNA methylation in its promoter region. Thus, their investigation effectively validated the involvement of  DNMT1 ‐mediated DNA methylation while elucidating a novel regulatory pathway involving  miR‐152/DNMT1/PTEN  in BCa. Consequently, these findings offer potential prospects for diagnostic and therapeutic targets in BCa [ 124 ].\nmiR‐148a  exhibits a reduction in urothelial carcinoma of the bladder (UCCB) cell lines, and its upregulation resulted in a decline in cell viability attributed to enhanced apoptosis rather than a suppression of proliferation. Furthermore,  miR‐148a  partially modulates this impact by downregulating the expression of  DNMT1 . Notably, combined treatment of  miR‐148a  and either cisplatin or doxorubicin in cells exhibits an additive or synergistic effect on inducing apoptosis. In this manner,  miR‐148a  exhibits tumour‐suppressive properties in UCCB, and the  miR‐148a/DNMT1  axis holds promising potential as an innovative therapeutic approach for addressing this particular malignancy [ 125 ].\nmiR‐424  significantly upregulated upon inhibition of  DNMT1  in BCa cells. Additionally, an inverse correlation exists between  miR‐424  staining and the immunoreactivity of  DNMT1 , providing evidence for the pivotal involvement of  DNMT1  in suppressing  miR‐424  expression. Notably, elevated levels of  miR‐424  suppressed the tumour growth rate and invasive potential, as examined both in vitro and in vivo. Furthermore, the EGFR pathway transmits the  miR‐424  signal, which governs cellular growth and EMT. Consequently, these findings emphasise the prospective significance of the  miR‐424/DNMT1  axis as a molecular prognosticator and therapeutic target in the context of BCa [ 126 ].\nRecent experimental investigation revealed downregulation of  DBCCR1‐003  and  DBCCR1 , alongside an upregulation of  DNMT1  and  DBCCR1  gene promoter hypermethylation in both BCa tissues and the T24 cell line. Furthermore, silencing  DNMT  via 5‐aza‐2‐deoxycytidine (DAC) or enhanced expression of  DBCCR1‐003  resulted in  DBCCR1  overexpression within T24 cells, achieved through the reversal of promoter hypermethylation and the disruption of  DNMT1  binding to the  DBCCR1  promoter. Notably, a physical association exists between  DBCCR1 ‐ 003  and  DNMT1 . Moreover, it was observed that the binding between these two molecules increased when the methylation of the  DBCCR1  promoter was inhibited. These findings suggest that  DBCCR1 ‐ 003  has the potential to bind with  DNMT1  and impede the  DNMT1 ‐mediated methylation process of  DBCCR1  [ 127 ].\nOesophageal cancer is the predominant malignancy in the gastrointestinal (GI) system and is characterised by suboptimal prognosis and survival rates. Over recent decades, numerous endeavours have been undertaken to identify efficacious therapeutic strategies; however, these approaches have encountered various challenges. Therefore, the identification of novel molecular biomarkers plays a pivotal role in the exploration of alternative therapeutic strategies for the management of these malignancies [ 128 ].\nmiR‐148a‐3p  directly targets  DNMT1 , and a negative correlation exists between the expression levels of  miR‐148a‐3p  and  DNMT1  in the context of oesophageal cancer. Excessive expression of  miR‐148a‐3p  in oesophageal cancer cells triggers inhibition of proliferation and invasion, as well as an enhancement of apoptosis. This suggests that  miR‐148a‐3p  potentially governs cell proliferation and invasion in oesophageal cancer by selectively targeting  DNMT1 . Hence, the  miR‐148a‐3p / DNMT1  axis holds promise as a prospective therapeutic target for future interventions [ 129 ].\nMiR‐124  is abundantly present as a miRNA in the brain, yet its expression is observed across diverse human and animal tissues, contributing to various disorders, including cancer [ 130 ]. The expression levels of  miR‐124‐3p  significantly decrease in oesophageal squamous cell carcinoma (ESCC) tissues, demonstrating a strong association with the increased proliferation and migration capabilities of ESCC. In ESCC tissues and cell lines, direct targeting of the mRNA 3′UTR region of  BCAT1  by  miR‐124‐3p  was detected. Furthermore, a regulatory pathway governs the expression of  miR‐124‐3p  in ESCC, explicitly implicating the involvement of  DNMT1 ‐mediated hypermethylation‐induced silencing. Notably,  DNMT1  displayed augmented expression levels within ESCC tissues and cell lines. Consequently, the  DNMT1/miR‐124/BCAT1  axis governs the advancement and advancement of ESCC [ 131 ].\nMiR ‐ 126 , situated in the 7th intron of  EGFL7  on human chromosome 9, has been implicated in the pathogenesis of GI malignancies [ 132 ]. In ESCC,  miR‐126  exhibited substantial downregulation, and diminished expression of  miR‐126  was attributed to promoter hypermethylation impacting its host gene,  Egfl7 . Also,  DNMT1  abnormally increased in ESCC, which led to the excessive methylation of  Egfl7 . Interestingly,  miR‐126  upregulation resulted in the suppression of  DNMT1 , suggesting the presence of a regulatory feedback loop. Also, it was found that  miR‐126  directly targets  ADAM9 . Furthermore,  miR‐126  ectopic expression or repression of  ADAM9  resulted in diminished cellular proliferation and migration in ESCC, accomplished through the restraint of epidermal growth factor receptor‐AKT signalling. In this manner,  miR‐126  holds promise as a prognostic marker for ESCC and proposes the involvement of a novel ‘ DNMT1 ‐ miR‐126  epigenetic circuit’ in the progression of ESCC [ 133 ].\nLUCAT1  expression displays upregulation in ESCC cell lines and cancerous tissue relative to normal cells and adjacent non‐malignant tissues. Silencing LUCAT1 in KYSE‐30 cells by decreasing DNA methylation exhibited a decrease in cellular proliferation, initiation of apoptosis and upregulation of tumour‐suppressor genes. Furthermore, the knockdown of  LUCAT1  resulted in a decline in DNMT protein levels, while transcription remained unaffected. Mechanistic investigation disclosed that  LUCAT1  plays a role in modulating the stability of  DNMT1 , leading to the inhibition of tumour suppressor gene expression via DNA methylation. Consequently, this molecular mechanism contributes to the initiation and metastasis of ESCC. In this manner,  LUCAT1/DNMT1  is a prospective candidate for pharmaceutical advancement and a discerning indicator for ESCC [ 134 ].\nThe high prevalence and fatality rate of CC, a condition specific to females, has prompted scientists to contemplate innovative approaches and formulate novel treatment protocols and strategies [ 135 ].\nChen et al. investigated the involvement of  miR‐148a‐3p  in CC. They revealed a notable reduction in the expression levels of  miR‐148a‐3p  within CC tissues compared to normal cervical tissues. They observed a significant decrease in the growth rate of CC cells upon the increased expression of  miR‐148a‐3p . Their luciferase reporter assay successfully identified  DNMT1  as the specific target gene regulated by  miR‐148a‐3p . Also, a negative association exists between the expression levels of the undifferentiated embryonic cell transcription factor‐1 ( UTF1 ) and the expression levels of  DNMT1  in CC tissues. Thus,  DNMT1  silencing resulted in an elevation of  UTF1  expression and reduced  UTF1  promoter methylation levels. These findings provide evidence for the regulatory role of  DNMT1  methylation in modulating the expression levels of  UTF1  in CC cells. Collectively,  miR‐148a‐3p  potentially hinders the growth of CC cells by modulating the expression levels of  DNMT1/UTF1 , thereby offering promising therapeutic targets for CC [ 136 ].\nChen et al. investigated the biological significance of  lncRNA TCF7  in CC. They found that suppressing endogenous HPV‐16 E6 had a significant inhibitory effect on  DNMT1  expression. Furthermore, silencing  DNMT1  triggers a notable augmentation in  miR‐155  expression levels. They elucidated that  miR‐155  directly targets 3′ UTR  TCF‐7 . Additionally, it was disclosed that restraining  TCF‐7  activity resulted in suppressed migratory capabilities of CC cells. Further in vivo investigation disclosed that suppressing  LncRNA TCF7  effectively mitigates the growth rate of CC cells. In this manner, the  miR‐155/DNMT1/TCF‐7  axis exhibits potential regulatory capabilities over the migration processes of CC cells, thereby indicating its significance as a crucial regulator in the development of CC [ 137 ].\nLINP1  expression increases in CC tissues compared to adjacent normal tissue and healthy human cervical epithelial cell lines (HUCEC). Surprisingly,  LINP1  reduction markedly suppressed the proliferative capacity of CC cells, facilitated apoptosis and substantially impeded the  vivo  growth of CC tumours. Additionally,  LINP1  plays a critical role in the recruitment of  DNMT1 ,  LSD1  and  EZH2  by  LINP1 , consequently leading to diminished expression levels of  PRSS8  and  KLF2 . So, the downregulation of  LINP1  resulted in both  KLF2  and  PRSS8  overexpression within CC cells. Further, increased expression of  PRSS8  and  KLF2  restrains cellular proliferation while promoting cellular apoptosis in CC. Additionally, inhibition of  KLF2  and  PRSS8  counteracted the suppressive effects on cell proliferation induced by the silencing of  LINP1 . Therefore,  LINP1  promotes CC progression by recruiting  DNMT1  and inhibiting  KLF2  and  PRSS8 . In this manner, targeting  LINP1  may hold significant potential as a therapeutic approach for treating CC [ 138 ].\nHead and neck squamous cell carcinoma (HNSCC) is the prevailing histological neoplasm originating within the head–neck region. Despite the implementation of surgical interventions, radiotherapy and chemotherapy for advanced stages (3 and 4), the 5‐year survival rate remains notably low. Consequently, a pressing imperative exists to innovate novel diagnostic methodologies and targeted therapeutic approaches [ 139 ].\nLi et al. explored the involvement of the  DNMT1/miR‐142‐3p/ZEB2  axis in nasopharyngeal carcinoma (NPC). Their in silico findings initially identified  miR‐142‐3p  as the most strongly associated with distant‐metastasis‐free survival and exhibiting downregulation in paraffin‐embedded NPC samples displaying distant metastasis. Additionally, the  miR‐142  locus exhibits hypermethylation in metastatic NPC and is correlated with the  miR‐142‐3p  reduction. Further, the silencing of  miR‐142‐3p  through epigenetic mechanisms involving  EZH2 ‐mediated recruitment of  DNMT1  resulted in the suppression of NPC cell metastasis.  ZEB2  serves as a specific and functionally significant target of  miR‐142‐3p  in NPC. Consequently,  miR‐142‐3p  functions as a crucial suppressive modulator in the metastasis of NPC while also uncovering a  DNMT1 ‐mediated epigenetic mechanism responsible for  miR‐142‐3p  inhibition [ 140 ].\nJili et al. focused on exploring the biological significance of the  DNMT1/miR‐148‐3p/RUNX3  axis in Laryngeal squamous cell carcinoma (LSCC). They observed a significant reduction and increased methylation of the  RUNX3  gene in LSCC compared to the corresponding normal tissue. They further observed that the RUNX3‐enforced expression suppressed LSCC cell migration and proliferation, while  RUNX3  suppression had the opposite effect. They discovered a regulatory relationship between  miR‐148a‐3p  and  RUNX3 , where they observed a significant reduction in the expression level of miR‐148a‐3p, which was positively associated with the expression of  RUNX3  in LSCC. They additionally determined that  miR‐148a‐3p  selectively targeted  DNMT1  within the context of LSCC. They subsequently revealed that  DNMT1  suppression resulted in  RUNX3  overexpression while concurrently impeding the migratory and proliferative capacities of LSCC cells. In summary,  miR‐148a‐3p  can influence the expression of  RUNX3  by altering  DNMT1 ‐mediated DNA methylation in LSCC [ 141 ].\nMelanoma, the most lethal variant of skin cancer, presents ongoing hurdles in its management, encompassing the need for precise prognostication of individuals amenable to adjuvant therapies and the timely identification of relapses. The difficulties have stimulated inquiry into biomarkers that hold the potential to serve as a therapeutic, prognostic and diagnostic aid [ 142 ].\nYu et al. examined the  DNMT1/miR‐211/RAB22A  axis in melanoma. They initially validated the expression of  miR‐211  in melanoma cell lines and noted a positive correlation between its reduction and enhanced  DNMT1  expression. Their experimental findings provided substantiation for a negative association between  DNMT1  and  miR‐211  expression and the ability of  DNMT1  to regulate DNA methylation in the  miR‐211  promoter region. Additionally, they identified a direct interaction between  miR‐211  and  RAB22A  while establishing the inhibitory impact of  miR‐211  on  RAB22A  expression. They also observed that  RAB22A  silencing enhanced epithelial characteristics and compromised mesenchymal features in melanoma cells, indicating that  miR‐211  regulates the process of EMT in melanoma cells by negatively regulating  RAB22A . So  DNMT1 ‐mediated promoter methylation functions to suppress miRNA activity within melanoma. Furthermore,  miR‐211  functions as a tumour suppressor in melanoma by negatively regulating  RAB22A . Therefore, the  DNMT1/miR‐211/RAB22A  axis offers a fresh perspective on the aetiology of melanoma, specifically concerning its involvement in the EMT pathway [ 143 ](Table  1 ).\nMajor miRNAs and their relationship in human cancer.\n\nDespite considerable advancements in comprehending the genetic factors implicated in cancer pathogenesis, numerous obstacles persist in the realm of cancer therapeutics, posing a formidable threat to the well‐being and mortality rates of individuals who have cancer worldwide. Hence, there is a pressing need to introduce fresh perspectives to understand better the underlying mechanisms that contribute to treatment resistance in tumour therapy. By understanding these mechanisms comprehensively, novel therapeutic approaches can be devised and implemented in the foreseeable future. Recent scientific investigations illustrated the pivotal role of the ncRNA‐ DNMT1  axis in regulating therapy resistance by influencing various biological processes [ 147 ]. Therefore, the present review focuses on the ncRNA‐ NMT1  axis in the therapy resistance of tumours.\nHan et al. explored the involvement of the  miR‐30  family in the resistance of OC cells to cisplatin. Within their study, they observed that  miR‐30c‐5p  and  miR‐30a‐5p  exhibited a substantial reduction in cisplatin‐resistant CP70 cells. This decrease was attributed to the induction of aberrant methylation caused by increased  DNMT1 . They additionally observed that  miR‐30a/c‐5p  exerted direct inhibitory effects on Snail and  DNMT1 . Further,  miR‐30a/c‐5p  enforced expression or the suppression of  DNMT1  and Snail enhanced sensitivity to cisplatin and a partial reversal of EMT in CP70 cells. In contrast,  miR‐30a/c‐5p  suppression or the  DNMT1  and Snail ectopic expression triggered cisplatin resistance and partial EMT in cisplatin‐sensitive A2780 cells. Notably, a reciprocal relationship exists between  miR‐30a/c‐5p  and  DNMT1 , a robust indicator of cisplatin resistance and EMT in ovarian cancer. This finding highlights a prospective target for enhancing anti‐cancer therapy [ 148 ]. In addition, Xiang et al. observed a notable downregulation of two specific microRNAs, namely  miR‐185  and  miR‐152 , in cisplatin‐resistant ovarian cell lines A2780/DDP and SKOV3/DDP, when compared to their respective sensitive parent lines A2780 and SKOV3. They revealed that upregulation of  miR‐152  or miR‐185 resulted in heightened sensitivity to cisplatin in A2780/DDP and SKOV3/DDP cells by impeding cell proliferation and facilitating apoptosis. Subsequently, they validated that these particular microRNAs exerted their effects by directly suppressing  DNMT1 . Importantly, administration of SKOV3/DDP cells with  miR‐152  mimics via intraperitoneal injection in CD‐1/CD‐1 nude mice resulted in an observed enhancement of cisplatin sensitivity within an in vivo context. Furthermore, their survival assays in A549 and HepG2 cells indicated that the microRNAs implicated in cisplatin sensitivity exhibited cell type‐specific associations. So, the  miR‐152 / miR‐185 / DNMT1  axis is involved in both in vitro and in vivo cisplatin resistance in OC [ 149 ]. Moreover, Sui et al. explored the biological significance of  miR‐148b  in the progression of chemoresistance within lung cancer. Their findings exhibited a decrease in the  miR‐148b  expression and an increase in  DNMTs  expression in cisplatin‐resistant human NSCLC cell lines, namely SPC‐A1/DDP and A549/DDP, in comparison to their parental counterparts SPC‐A1 and A549. Overexpression of  miR‐148b  resulted in a reduction in  DNMT1  expression, enhanced cellular sensitivity to cisplatin and promoted cisplatin‐induced apoptosis in SPC‐A1/DDP and A549/DDP cells. In addition, silencing  miR‐148b  resulted in  DNMT1  upregulation, alongside a reduction in cell sensitivity to cisplatin treatment in SPC‐A1 and A549 cells. They subsequently revealed that  miR‐148b  suppresses  DNMT1  expression by targeting the 3'UTR in A549 and A549/DDP cell lines. Notably,  DNMT1  silencing enhances the susceptibility of A549/DDP cells to cisplatin, while  DNMT1  upregulation counteracts the pro‐apoptotic impact induced by the introduction of  miR‐148b  mimic. Consequently,  miR‐148b  effectively counteracts the resistance to cisplatin in non‐small cell cancer cells by negatively modulating the expression of  DNMT1  [ 150 ].\nCongras et al. explored the involvement of  miR‐125b  in the progression of doxorubicin resistance in nucleophosmin‐anaplastic lymphoma kinase (NPM‐ALK) (+) anaplastic large‐cell lymphoma (ALCL). Their findings indicate that the expression of miR‐125b is reduced in NPM‐ALK (+) cell lines and samples obtained from patients, primarily due to hypermethylation occurring within its promoter region. In their investigation, they observed that the activity of NPM‐ALK, in conjunction with DNA topoisomerase II (Topo II) and  DNMT1 , plays a pivotal role in  miR‐125b  silencing through DNA hypermethylation. Interestingly, they found that  miR‐125b  silencing could be effectively counteracted by inhibiting DNMTs using decitabine or by obstructing DNA Topo II's function using doxorubicin or etoposide. Additionally, they revealed that doxorubicin administration in NPM‐ALK (+) cell lines resulted in elevated levels of  miR‐125b  through the inhibition of the  DNMT1  binding to the  MIR125B1  promoter and the subsequent downregulation of  BAK1 , a target gene associated with pro‐apoptotic activities. They subsequently revealed that reversing  miR‐125b  suppression, enhancing  miR‐125b  concentrations and diminishing  BAK1  expression exhibited a correlation with the reduced effectiveness of doxorubicin, implying the presence of a pharmacoresistance mechanism. The  DNMT1/miR‐125b  pathway holds potential as a biomarker for resistance in cases of ALK (+) ALCL [ 151 ].\nZhou et al. explored the potential correlation between the  DNMT1/miR‐20a  axis and the sensitivity of glioma cells to temozolomide (TMZ). They revealed that the expression of  DNMT1  was observed to be decreased, the methylation of the  miR‐20a  promoter was attenuated, and the levels of  miR‐20a  were elevated in TMZ‐resistant U251 cells compared to the parental U251 cells. It was observed that the reduction of TMZ sensitivity in U251 cells occurred due to methyltransferase silencing through treatment with 5‐aza‐2′‐deoxycytidine Additionally, they noted that in U251/TM cells, there existed an inverse relationship between  DNMT1  expression and  miR‐20a  expression, while a positive correlation was found between  DNMT1  expression and both TMZ sensitivity and leucine‐rich repeats and immunoglobulin‐like domains 1 expression. These effects were subsequently reversed upon alterations in  miR‐20a  expression. In their study,  DNMT1  upregulation increased apoptotic events in U251/TM cells, which was counteracted by  miR‐20a  mimic. Conversely, the  DNMT1  suppression mitigated U251/TM cell apoptosis, and this effect was nullified upon treatment with a  miR‐20a  inhibitor. They finally disclosed that pretreatment with pcDNA‐DNMT1 suppressed the growth of U251/TM xenograft tumours, while pretreatment with  DNMT1 ‐small hairpin RNA enhanced their growth. In summary,  DNMT1  facilitated chemosensitivity by attenuating methylation levels in the promoter region of  miR‐20a  within glioma cells [ 152 ](Figure  3 ).\nA schematic representation of miRNAs/DNMT1 axis in cancer therapy resistance.\n\nStem cells possess two pivotal characteristics, specifically the capacity for self‐renewal and the potential to undergo differentiation into various cell lineages endowed with distinct functional roles. These inherent attributes are also exhibited by cancer stem cells (CSCs). These cells have been identified in various cancer types, contributing to tumour formation. A recent study revealed that the axis involving ncRNA and  DNMT1  plays a crucial role in regulating the activity of CSCs. Therefore, in the following section, we explain the effects of the ncRNA‐ DNMT1  axis on CSC activity and their impact on tumorigenesis [ 153 ].\nLCSCs displayed increased  DNMT1  activity and expression, reduced  miR‐34a  expression accompanied by enhanced promoter methylation, and heightened stemness properties compared to the original liver cancer cells. Also,  DNMT1  silencing resulted in the repression of  DNMT1  itself, accompanied by an increase in  miR‐34a  levels through demethylation of its promoter region. This inhibition also led to a reduction in stemness characteristics within LCSCs. Furthermore, overexpression of  miR‐34a  resulted in the repression of stemness properties, while silencing  miR‐34a  exert opposite effects. Furthermore, overexpression of  miR‐34a  successfully mitigated the impact of elevated  DNMT1  levels on the stem cell characteristics of LCSCs while leaving  DNMT1  expression unaffected. Ultimately,  FOXM1  serve as a direct target of miR‐34a within LCSCs. Therefore,  DNMT1's  abnormal activity results in promoter methylation and subsequent repression of miR‐34a, thereby leading to  FoxM1  overexpression through the promotion of LCSC stemness. Thereby, inhibition of  DNMT1/miR‐34a ‐mediated  FOXM1  overexpression could potentially suppress liver cancer by selectively targeting LCSCs [ 154 ]. Also,  DNMT1/miR‐34a  axis plays a crucial role in regulating osteosarcoma cancer stem‐like cells (OSLCs). In this regard, higher  DNMT1  levels, primarily through the induction of methylation in the miR‐34a promoter, significantly reduce its expression and are associated with increased stemness of OSLCs. Moreover, silencing  DNMT1  is associated with demethylation of the  miR‐34a  promoter and upregulation of miR‐34a expression, which leads to the suppression of stemness in OSLCs in a dose‐dependent manner. Thereby, abnormal activation of  DNMT1  induces promoter methylation of  miR‐34a , resulting in its downregulation, thereby enhancing and maintaining the stemness characteristics of OSLCs [ 155 ].\nAccording to recent experimentation, high  SALL4  expression is associated with lower progression‐free survival (PFS) rates, and  SALL4  inhibition led to diminished capabilities of colony formation, proliferation, drug resistance and migration in vitro. Furthermore, there is a direct and inverse relationship between  miR‐497‐5p  and  SALL4 . Moreover, suppression of  miR‐497‐5p  led to the enhancement of stem‐like properties in choriocarcinoma CSLCs. In addition, increased expression of  SALL4  and  miR‐497‐5p  reduction facilitates the progression of choriocarcinoma within an in vivo. Notably,  DNMT1 / 3B  overexpression, facilitated by the upregulation of  SALL4 , hindered the expression of miR‐497‐5p by promoting hypermethylation. Thus, the  miR‐497‐5p/SALL4/DNMT1/3B  axis emerged as a critical factor in fostering the stemness phenotype of choriocarcinoma [ 156 ].\nPancreatic CSCs, irrespective of their heterogeneity or polyclonality within the analysed tumours, exhibit elevated levels of  DNMT1  activity and DNA methylation. Moreover, applying pharmacological or genetic methods to target  DNMT1  in CSCs specifically decreased their self‐renewal and in vivo tumour formation capacity. These findings establish  DNMT1  as a promising therapeutic target for CSCs. Further, the  miR‐17‐92  cluster, which consists of six individual members ( miR‐17 ,  18a ,  19a ,  19b ,  20a  and  92a ), exhibited hypermethylation in CSCs compared to non‐CSCs. Additionally,  miR‐17‐92  upregulation decreased CSC self‐renewal potential, in vivo tumour formation ability, and resistance to chemotherapy. Furthermore, suppression of the  miR‐17‐92  cluster in differentiated cells resulted in a contrasting outcome, inducing non‐CSCs to exhibit characteristics resembling CSCs. In this manner,  DNMT1  primarily functions by repressing the  miR‐17‐92  cluster, significantly influencing PDAC CSCs maintenance. These results highlight the  DNMT1 / miR‐17‐92  cluster axis as a critical regulator of biological processes in CSCs and offer a compelling basis for developing epigenetic modifiers to target CSC plasticity [ 157 ].\nThere is a notable upregulation of  BCL11A  in TNBC, while the expression of  miR ‐ 137  is significantly decreased in both TNBC tissues and cell lines. The expression of  BCL11A  is downregulated at both the mRNA and protein levels by  miR‐137  through direct targeting of its 3′ UTR. Additionally, upregulation of  miR‐137  or silencing of  BCL11A  resulted in a decrease in the number of tumorspheres and the proportion of CSCs in both MDA‐MB‐231 and SUM149 cell lines, while also exerting an inhibitory effect on tumour growth in vivo. Additionally, an interaction exists between  BCL11A  and  DNMT1  within TNBC cells. Notably, the inhibition of either  DNMT1  or  BCL11A  results in a compromised capacity for cancer stemness and tumorigenesis in TNBC, which is achieved through the suppression of ISL1 expression both in vivo and in vitro. Furthermore,  miR‐137  disrupts the interaction between  BCL11A  and  DNMT1 , reducing cancer stemness and inhibiting tumour progression in TNBC [ 158 ].\nDing et al. explored the impact of the  miR‐126/DNMT1  axis on the proliferation and growth of leukaemia stem cell (LSC) lines, including MOLM13‐LSCs and KG‐1a‐LSCs. They firstly indicated a notable upregulation of  miR‐126  expression in both CD34+ cells and the aforementioned LSC lines. They observed that  miR‐126  silencing in MOLM13‐LSCs and KG‐1a‐LSCs impeded cellular proliferation while enhancing apoptosis. They further substantiated that  miR‐126  directly interacts with  DNMT1  and exerts negative regulatory control over its expression. Thereby,  miR‐126  enhances the proliferative capacity of LSCs by regulating  DNMT1  [ 159 ](Figure  4 ).\nA schematic representation of miRNAs/DNMT1 axis in cancer stem cells.\n\nRecent empirical evidence indicated the role of the ncRNA/ DNMT1  axis in advancing malignant tumours. Consequently, this axis holds significant promise as a viable target for therapeutic intervention in managing human neoplastic conditions. Multiple ncRNA/ DNMT1  axis regulators have been formulated as potential interventions in cancer therapy. In the subsequent section, we delve into the significance of the ncRNA/ DNMT1  axis as a focal point for various remedies to combat malignancies in human beings.\nThere has been a growing global acceptance of herbal medicines in recent years, leading pharmaceutical companies to actively explore them as valuable reservoirs for exploring novel drugs [ 160 ]. Empirical investigations have revealed that herbal medicine exhibits the potential to regulate various ncRNAs and the  DNMT1  axis, which are closely associated with cancer. Consequently, this modulation mechanism holds promise in impeding the onset and progression of cancer. The genus Vitex encompasses 250 shrubs and trees, distributed predominantly across the tropical and subtropical regions, while several species inhabit temperate zones. Traditionally, Vitex species have been historically employed to alleviate various health conditions, including premenstrual issues, migraines, malignancies, diarrhoea, respiratory infections, rheumatic pain, GI ailments, sprains and inflammatory responses. Casticin (3′, 5‐dihydroxy‐3, 4′, 6, 7 tetramethoxyflavone), a flavonoid compound possessing a molecular formula of C19H18O8 and a molecular weight of 374.34, holds significance in this regard. A commercially accessible variant of casticin (98% purity) derived from  \n V. trifolia \n  is readily obtainable in an analytically graded form. Casticin, a bioactive compound, has been extracted from different plant tissues within the Vitex genus, including the fruits and leaves of  \n V. trifolia \n , aerial parts and seeds of  \n V. agnus‐castus \n , and leaves of  \n V. negundo \n . Recent studies demonstrated that casticin displays apoptosis and antiproliferation activity. This compound has shown effectiveness against numerous cancer cell lines through diverse molecular mechanisms [ 161 ]. CAS exhibited a selective decrease in the viability of HCC cells while having no discernible effect on L02 cells. Additionally, CAS demonstrated the ability to impede the stemness characteristics within HCC cells. CAS could suppress the activity and expression of  DNMT1  while simultaneously upregulating the levels of miR‐148a‐3p. Furthermore, the influence of CAS on stemness traits was nullified when  DNMT1  was stably overexpressed, whereas  miR‐148a‐3p  upregulation augmented the diminishing effect of CAS on stemness features. Further,  DNMT1  upregulation facilitated hypermethylation of the  miR‐148a‐3p  promoter, subsequently suppressing its expression. Additionally,  miR‐148a‐3p  effectively restrained DNMT1 expression by selectively binding to the 3′‐UTR of  DNMT1  mRNA. In the context of in vivo nude mouse xenograft experiments, agomir‐148a‐3p and CAS exhibited substantial efficacy in inhibiting tumour growth, surpassing the individual activities of either molecule. In this manner, CAS could impede stemness properties in HCC cells through its disruption of the mutual negative modulation between  miR‐148a‐3p  and  DNMT1  [ 162 ]. Importantly, the botanical remedy known as Rhizoma of Paris polyphyllin, a component of Traditional Chinese Medicine, has gained significant recognition among herbal healthcare professionals for its extensive use in treating various tumour types, such as those affecting the liver, urinary bladder and pancreas. Polyphyllin I (PPI), a steroidal saponin, has been extensively investigated as a prominent active constituent of Rhizoma of Paris. It has demonstrated noteworthy antitumor properties across various cancer types by impeding tumour cell proliferation, suppressing metastasis and eliciting cell cycle arrest and apoptosis via the mitochondrial pathway [ 163 ]. PPI exerted a substantial inhibitory effect on the proliferation and migration capabilities of CRPC cells while also inducing cell cycle arrest. Mechanistically, PPI led to a reduction in the expression of  HOTAIR ,  DNMT1  and  EZH2 . Intriguingly,  HOTAIR  silencing resulted in decreased protein expressions of  EZH2  and  DNMT1 . Conversely, the introduction of exogenous HOTAIR counteracted the inhibitory effects of PPI on  EZH2  and  DNMT1  protein expressions, as well as  EZH2  promoter activity and cell growth. Moreover, in vivo findings demonstrated that PPI triggers inhibition of tumour growth,  HOTAIR  and the protein expressions of  DNMT1  and  EZH2 . Therefore, PPI impedes the proliferation of CRPC cells by suppressing HOTAIR expression, subsequently leading to the repression of  DNMT1  and  EZH2  expressions. In this manner, the overall responses of PPI are influenced by the intricate interplay between  DNMT1 ,  HOTAIR  and  EZH2 , characterised by their mutual regulation and reciprocal effects [ 164 ].\nCurcumin, derived from the rhizome of the  \n Curcuma longa \n  plant and belonging to the polyphenolic class, has traditionally been utilised in medicinal practices as an agent with antioxidant and anti‐inflammatory properties [ 165 ]. However, the hydrophobic characteristics inherent to this phytochemical impose significant constraints on its ability to be effectively absorbed by cells and exert its biological effects. To surmount this challenge, a potentially efficacious strategy involves the incorporation of curcumin within dendrosome nanoparticles, which has recently been devised as dendrosomal nano‐curcumin (DNC) [ 166 ]. Chamani et al. explored the impact of DNC on the mir‐34 family member's expression in two HCC cell lines, Huh7 and HepG2. They demonstrated that DNC treatment induced upregulation of mir34a, mir34b and mir34c expression while concurrently downregulating the expression of DNMT1,  DNMT3A  and  DNMT3B  in both Huh7 and HepG2 cell lines. Also, the viability of Huh7 and HepG2 cells diminished by DNC administration, primarily by facilitating the reestablishment of  miR‐34 s  expression. So, DNC exerted its effect by downregulating DNMTs, thereby reactivating the epigenetically suppressed  miR‐34  family. In this manner, DNC could be a promising candidate for epigenetic therapy in HCC [ 167 ].\nOver the past 2 years, endeavours in synthetic biology have yielded innovative synthetic RNA constituents that can modulate gene expression within living organisms [ 168 ]. These advancements have laid the foundation for achieving scalable and customizable cellular functionality. The primary obstacles that need to be addressed in this nascent discipline involve elucidating strategies for effectively integrating computational and directed‐evolution techniques to enhance the intricacy of engineered RNA systems [ 169 ]. Additionally, there is a pressing need to explore avenues for the widespread application of these systems within mammalian contexts. PAS1‐30 nt‐RNA represents a chemically engineered PAS1 segment artificially created to incorporate enhancements in 2′‐O‐methylation and 5′‐cholesterol, specifically facilitating in vivo RNA transportation. In BC,  DNMT1  acts as a suppressor of PAS1 expression, and subsequent  DNMT1  silencing resulted in a noticeable increase in PAS1 levels. Additionally, protein PAS1 interacts with the RNA‐binding protein vigilin, preserving its overall stability. Furthermore, PAS1 facilitates the binding of H3K9me3 at the PH20 promoter through its interaction with SUV39H1, resulting in the repression of PH20. Importantly, in vivo and in vitro analysis revealed that PAS1 upregulation effectively impeded BC cell proliferation and metastasis. Combining decitabine with PAS1‐30 nt‐RNA significantly displays enhanced anti‐tumour effects, surpassing the efficacy observed with decitabine as a standalone treatment. The observed effectiveness of the combination is contingent not only upon the collaborative impacts of the DNMT inhibitor and PAS1‐30 nt‐RNA but also on the augmented expression of PAS1 instigated by the DNMT inhibitor. In this manner, in future BC treatment, a potential approach could involve the concurrent administration of decitabine and PAS1‐30 nt‐RNA, primarily targeting the modulation of  DNMT1 / PAS1 / PH20  interactions [ 170 ].\nMicroRNA molecules play a pivotal role in cancer progression and are progressively being implemented in clinical settings as targets and agents for therapeutic purposes [ 171 ]. A novel intervention strategy known as miRNA replacement has been recently devised, aiming to address the therapeutic potential of miRNAs. The rationale for advancing miRNA therapeutics is founded on the principle that rectifying these deficiencies in miRNAs through either antagonistic or restorative measures holds the potential to yield therapeutic advantages [ 172 ]. Therefore, we presented the most recent inquiries into the therapeutic approaches concerning the delivery of miRNAs. Specifically, Ding et al. examined the impact of miR‐200 family constituents and epigenetic alterations on preserving the mesenchymal/metastatic phenotype subsequent to EMT in HCC. They observed that mesenchymal cells following EMT exhibit significant upregulation of E‐box repressors  Zeb2  and  Zeb1 , alongside a simultaneous decrease in the expression of four members of the  miR‐200 family  (namely,  miR‐200a ,  miR‐200b ,  miR‐200c  and  miR‐429 ). Their further experimentation revealed the methylation of multiple CpG sites present within the  E‐cadherin  promoter region in mesenchymal cells. They also showed that  miR‐200b  enforced expression in these cells led to a noteworthy enhancement in  E‐cadherin  levels and a concurrent decrease in cell migration in vitro. On the contrary, their in vivo investigations demonstrated the absence of notable alterations in metastatic capacity after  miR‐200b  overexpression. Their subsequent experimentation unveiled that the combined administration of a DNMT inhibitor and  miR‐200b  overexpression led to a considerable reduction in the invasive characteristics and complete elimination of metastatic potential in mesenchymal cells. Additionally, it was revealed that the specific application of short hairpin RNA to target  E‐cadherin  directly did not lead to the restoration of metastatic capability following DNMT silencing and re‐expression of  miR‐200b . Furthermore, they disclosed that  E‐cadherin  restoration in primary mesenchymal cells proved insufficient in impeding metastatic potential. A practical approach to address liver cancer metastasis may involve a combined therapeutic strategy involving the modulation of miR‐200b expression and DNMT silencing without necessarily relying on  E‐cadherin  restoration [ 173 ]. Furthermore, Cai et al. examined the combined therapeutic impact of sorafenib and gold nanoparticles carrying anti‐ miR‐221  on HCC cell lines. Their investigation revealed that the administration of sorafenib in HepG2 and Huh7 cells triggered  miR‐221  signalling pathway activation, resulting in significant upregulation of  miR‐221  expression. They additionally validated the decrease in  p27  expression due to sorafenib treatment while observing a corresponding increase in  DNMT1  levels. They observed that increasing concentrations of AuNPs‐anti‐miR221 inhibited cell growth in both Huh7 and HepG2 cells. Moreover, the combined treatment of AuNPs‐anti‐miR221 and sorafenib led to a significant enhancement in cell growth inhibition. Additionally, they found that AuNPs‐anti‐miR221 exhibited a synergistic effect, further enhancing the inhibitory action of sorafenib. Their further experimentation disclosed that the administration of sorafenib in combination with AuNPs‐anti‐miR221 triggers elevated levels of p27 expression and reduced levels of DNMT1 expression. This signifies that AuNPs‐anti‐miR221 exhibits chemosensitizing properties when used in conjunction with sorafenib. Thereby, AuNPs‐anti‐miR‐221 could effectively augment the inhibitory impact of sorafenib on cell proliferation by deactivating the  miR‐221/p27/DNMT1  signalling pathway. Hence, it is plausible to consider AuNPs‐anti‐miR221 as a viable chemosensitizer in treating HCC when used with sorafenib [ 174 ]. Importantly, Indoleamine 2, 3‐dioxygenase (IDO) is an intracellular enzyme whose increased activity demonstrates a negative correlation with the presence of tumour‐infiltrating lymphocytes (TILs) in cases of oesophageal and endometrial cancers. Zhou et al. explored the impact of cancer‐secreted exosomal  miR‐142‐5p  on the immune status of cervical squamous cell carcinoma (CSCC). They initially demonstrated a positive association between elevated levels of  miR‐142‐5p  and indoleamine 2, 3‐dioxygenase (IDO) expression in lymphatic vessels associated with advanced CSCC. They observed that  miR‐142‐5p  is conveyed from CSCC‐secreted exosomes to lymphatic endothelial cells (LECs), leading to the depletion of CD8 + T cells through the enhancement of lymphatic indoleamine 2, 3‐dioxygenase (IDO) expression. This effect was negated when an IDO inhibitor was administered. Their mechanistic analysis demonstrated that  miR‐142‐5p  directly inhibits the expression of lymphatic AT‐rich interactive domain‐containing protein 2 ( ARID2 ). Furthermore, it hinders the recruitment of  DNMT1  to the interferon ( IFN)‐γ  promoter and amplifies the transcription of  IFN‐γ  by suppressing promoter methylation. Consequently, this cascade of events culminates in heightened IDO activity. They additionally observed a positive association between elevated levels of serum exosomal  miR‐142‐5p  and the advancement of CSCC, along with parallel increases in IDO activity. Therefore, CSCC cells release exosomes containing  miR‐142‐5p , which subsequently promote IDO expression in LECs through the  ARID2‐DNMT1‐IFN‐γ  signalling pathway, resulting in the suppression and depletion of CD8 +  T cells [ 175 ](Table  2 ).\nAn overview of different compounds targeting non‐coding RNAs and their potential influence on DNMT1 activity.\n\nDespite the notable progress made in diagnosis and treatment over recent decades, human cancer continues to pose a significant clinical obstacle owing to the lack of advancements in long‐term survival rates. Besides genetic change, disruption of epigenetic processes can also lead to altered gene function and malignant cellular transformation. Epigenetic enzymes such as  DNMT1  could lead to transcription repression by catalysing genomic DNA methylation and are usually aberrantly expressed in human tumours. Moreover, dysregulation of ncRNAs is linked to epigenetic reprogramming throughout tumour advancement, primarily attributable to their capacity to engage with DNMTs, notably  DNMT1 . In the current work, we noticed a reciprocal relationship between ncRNAs and  DNMT1 . Some miRNAs, including  miR‐185 ,  miR‐139‐5p  and  miR‐377 , could directly target  DNMT1 , whereas others, such as  miR‐378 ,  miR‐30b, miR‐34a ,  miR‐497  and  miR‐142  could be hypermethylated by  DNMT1  and downregulated. This dual regulatory mechanism further emphasises the complexity of miRNA‐ DNMT1  interactions and their relevance in cancer pathogenesis. Notably, the ncRNA‐ DNMT1  axis plays a critical role in mediating resistance to various chemotherapy agents, including cisplatin, doxorubicin and TMZ, by regulating the expression of essential miRNAs and promoting aberrant DNA methylation that impacts tumour cell sensitivity. In addition, the ncRNA‐ DNMT1  axis plays a crucial role in regulating CSCs activity, with multiple microRNAs, such as  miR‐34a  and  miR‐126 , modulating  DNMT1  expression to influence stemness characteristics and tumour progression across various cancers. Additionally, various therapeutic strategies, including herbal medicine, synthetic RNA molecules, DNC and miRNA replacement, have been implemented to modulate the ncRNA/ DNMT1  axis as part of cancer therapy approaches. However, one limitation of the current review article is that we mainly focused on two mechanisms by which lncRNAs regulate  DNMT1  function: first, by acting as molecular sponges for miRNAs, leading to increased  DNMT1  expression, and second, by functioning as scaffolds to recruit  DNMT1  to target miRNAs, resulting in their hypermethylation and suppression. However, lncRNAs can also operate through other approaches. For example, lncRNAs can interact with DNA and co‐transcriptionally form RNA–DNA hybrids, such as R‐loops, which are recognised by chromatin modifiers to either activate or inhibit target gene transcription, or by transcription factors. This mechanism, however, has not yet been studied in relation to  DNMT1 . Thus, one of the major limitations of the current work is that we did not cover all regulatory pathways related to lncRNAs in the regulation of  DNMT1 .\n\nRecent developments in gene editing technology have demonstrated promising approaches for precise and targeted DNA modification. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9, initially identified in  \n Escherichia coli \n , provides a powerful tool for precise genome editing. By utilising base complementary pairing, the CRISPR/Cas9 system offers a highly specific DNA modification. Recently developed CRISPR/Cas9‐based tools, namely CRISPR interference (CRISPRi), employ a catalytically dead Cas9 (dCas9) protein complexed with a transcriptional effector and a single guide RNA (sgRNA). This variant of dCas9 is unable to trigger DNA cleavage, yet it maintains its capacity for sequence‐specific DNA binding. The binding of a dCas9/sgRNA complex to a target gene sequence modulates transcriptional activity [ 176 ]. Another variant of the CRISPR system, known as CRISPR activation (CRISPRa), can be utilised to enhance the expression of lncRNA genes. Recent studies have highlighted the potential of CRISPRa in activating DANCR, which in turn promotes chondrogenic differentiation and improves calvarial bone healing [ 177 ]. So, applying CRISPR/Cas9 technology could restore the expression of downregulated ncRNAs, leading to epigenetic reprogramming in various diseases, such as cancer. In this manner, CRISPR‐based targeted activation of ncRNAs such as miRNAs and lncRNAs may provide an alternative therapeutic approach for cancers.\n\nSeyed Mohsen Aghaei‐Zarch:  conceptualization (lead), supervision (lead), visualization (equal), writing – original draft (equal), writing – review and editing (equal).  Ali Esmaeili:  conceptualization (supporting), validation (supporting), visualization (equal), writing – original draft (equal), writing – review and editing (equal).  Saeid Bagheri‐Mohammadi:  conceptualization (equal), supervision (equal), validation (equal), writing – original draft (equal), writing – review and editing (equal).\n\nThe authors have nothing to report.\n\nThe authors declare no conflicts of interest.","source_license":"CC-BY-4.0","license_restricted":false}