Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 346-357 http://medscipublisher.com/index.php/cge 351 While DNMTs are crucial for maintaining global methylation patterns and preventing genomic instability, their aberrant activity in HCC often leads to selective hypermethylation of specific genes alongside hypomethylation in other regions, resulting in oncogene activation and increased mutation rates (Zhang et al., 2020). Among these, DNMT3B has been identified as particularly significant in HCC. Studies have shown that DNMT3B is significantly upregulated in liver cancer tissues compared to normal liver tissues, indicating that it may drive the abnormal DNA methylation patterns seen in this malignancy (Szparecki et al., 2016). Targeting DNMTs with specific inhibitors has become a key focus in epigenetic therapy for HCC, aiming to reverse aberrant methylation patterns and reactivate silenced tumor suppressor genes, thereby inhibiting tumor growth. 4.2 TET enzymes and DNA demethylation TET enzymes (Ten-eleven translocation proteins) are crucial for the active demethylation process, converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products, ultimately leading to the removal of methyl groups. The function of TET enzymes, particularly TET1 and TET2, is often dysregulated in HCC, contributing to the persistence of hypermethylated and silenced states in tumor suppressor gene promoters (Tu et al., 2015). Reduced expression of TET enzymes in HCC has been correlated with decreased levels of 5hmC, leading to an imbalance between methylation and demethylation activities. This imbalance can result in the repression of genes involved in cellular differentiation and apoptosis, contributing to the malignant transformation of liver cells (Song et al., 2022). The downregulation of TET enzymes, coupled with the overactivity of DNMTs, creates a methylation environment that favors cancer progression. Research into reactivating TET enzymes or enhancing their activity through epigenetic drugs is ongoing, as restoring normal levels of DNA demethylation might help to reactivate tumor suppressor genes and suppress tumor growth (Cheng et al., 2021). This therapeutic strategy aims to rebalance the epigenetic landscape in HCC, potentially offering a novel approach to treat this aggressive cancer. 4.3 Non-coding RNAs and DNA methylation Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play a pivotal role in regulating DNA methylation and gene expression in HCC. LncRNAs can interact with DNMTs to guide them to specific genomic loci, leading to targeted gene silencing through DNA methylation (Yang et al., 2022). For example, certain lncRNAs can recruit DNMT1 to the promoters of tumor suppressor genes, resulting in their methylation and subsequent downregulation. MicroRNAs, such as miR-30a-3p, have been shown to target DNMT3A, modulating its expression and thus influencing the methylation status of specific genes in HCC (Wei et al., 2019). By reducing the levels of DNMT3A, miR-30a-3p can help to alleviate the hypermethylation of tumor suppressor gene promoters, leading to their reactivation and providing a potential therapeutic avenue for HCC. Some lncRNAs are involved in the regulation of TET enzymes, thereby influencing DNA demethylation processes. LncRNAs can interact with TET proteins to facilitate or inhibit their activity, affecting the balance between methylation and demethylation in liver cancer cells (Yang et al., 2022). These interactions underscore the complexity of epigenetic regulation in HCC and highlight the potential of targeting non-coding RNAs as part of therapeutic strategies to restore normal methylation dynamics. These molecular players—DNMTs, TET enzymes, and non-coding RNAs—form a complex regulatory network that governs DNA methylation and gene expression in liver cancer. Their interactions present opportunities for targeted therapies aimed at reversing abnormal methylation patterns and controlling tumor progression. 5 Functional Implications of DNA Methylation in Liver Cancer 5.1 Tumor suppressor gene silencing One of the primary consequences of aberrant DNA methylation in HCC is the silencing of tumor suppressor genes through hypermethylation of promoter regions. Genes like p16, RASSF1A, and GSTP1, which are critical for cell
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