Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 346-357 http://medscipublisher.com/index.php/cge 348 Additionally, aberrant DNA methylation is associated with increased resistance to chemotherapy and higher risks of cancer recurrence. In certain cancers, these methylation changes can disrupt the function of DNA repair genes, leading to resistance to radiation and chemotherapy (Maurano et al., 2015). Understanding these abnormal methylation patterns is crucial for developing early diagnostic tools and personalized treatment strategies in oncology. 3 Role of DNA Methylation in Liver Cancer Pathogenesis 3.1 Aberrant methylation patterns in liver cancer In HCC, aberrant DNA methylation patterns include global hypomethylation and promoter-specific hypermethylation. Global hypomethylation contributes to genomic instability, which increases mutation rates and activates oncogenes, thus promoting the uncontrolled proliferation of liver cancer cells (Zheng et al., 2018). For example, hypomethylation can reactivate genes that are normally silenced in healthy liver cells, driving the progression of cancer. Conversely, hypermethylation in promoter regions can suppress the expression of key tumor suppressor genes, leading to loss of cell cycle control and inhibition of apoptosis. These genes include p16, RASSF1A, and GSTP1, which are often hypermethylated in HCC, resulting in their functional loss (Zhang et al., 2016). This promoter hypermethylation is frequently observed in the early stages of HCC development and plays a critical role in tumor formation. Recent advances in whole-genome bisulfite sequencing have provided a comprehensive view of the methylation landscape in HCC, revealing numerous differentially methylated regions associated with changes in gene expression. Studies have shown that hypermethylation of specific gene promoters is closely associated with HCC progression, and these methylation changes hold promise as potential biomarkers for early diagnosis and prognosis (Yan et al., 2021). These findings offer an important foundation for early screening and personalized treatment strategies for HCC. 3.2 Epigenetic drivers of hepatocarcinogenesis In hepatocellular carcinoma (HCC), epigenetic regulators like DNA methyltransferases (DNMTs) and TET enzymes are pivotal in controlling DNA methylation levels, thereby influencing gene expression and tumor progression. Elevated expression of DNMT1 and DNMT3B, as shown in the correlation and prognostic analysis, is associated with increased promoter methylation of tumor suppressor genes, leading to their silencing. This epigenetic silencing promotes uncontrolled cell proliferation and inhibits apoptosis, contributing to tumor development and progression. The interaction network and survival analysis in Figure 1 further indicate that DNMT1 and DNMT3B are risk factors for overall survival (OS) in HCC patients, and their high expression is associated with poor prognosis. These alterations are evident not only in malignant liver tissues but also in precancerous conditions like cirrhosis, suggesting that DNMT-mediated methylation changes play a role even in the early stages of hepatocarcinogenesis. This highlights their potential as both biomarkers for early detection and therapeutic targets in HCC (Pan et al., 2023). The TET family of enzymes, which converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), is essential for DNA demethylation. This demethylation process is critical for maintaining normal gene expression; however, in HCC, altered expression or function of TET enzymes often leads to an accumulation of hypermethylated states, further suppressing key genes involved in differentiation and apoptosis (Song et al., 2022). This imbalance between methylation and demethylation is a key driver of HCC pathogenesis. Moreover, recent studies have identified that specific non-coding RNAs, such as long non-coding RNAs and microRNAs, interact with DNMTs and TETs to regulate DNA methylation levels, thus influencing gene expression in HCC (Wang et al., 2020). The involvement of these non-coding RNAs adds complexity to the regulation of methylation in liver cancer and presents new potential therapeutic targets for future research.
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