Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 346-357 http://medscipublisher.com/index.php/cge 350 Environmental factors such as exposure to aflatoxins, chronic alcohol consumption, and diets deficient in methyl donors have been shown to affect the one-carbon metabolism pathway, leading to altered DNA methylation levels (Zheng et al., 2016). These exposures can result in global hypomethylation alongside site-specific hypermethylation, creating an environment that favors malignant transformation. For instance, aflatoxin exposure has been specifically linked to mutations in the p53 gene and associated DNA methylation changes in liver tissues. Additionally, metabolic dysregulation within liver cancer cells is associated with changes in DNA methylation. Abnormal tumor cell metabolism can impact levels of S-adenosylmethionine (SAM), a key methyl donor required for DNA methylation reactions (Yan et al., 2021). Reduced levels of SAM may lead to global hypomethylation, while liver cancer cells with high metabolic activity may selectively maintain hypermethylation at critical promoters through alternative pathways. The interplay between altered metabolism and methylation regulation is a critical component of the epigenetic landscape in HCC. 4 Key Molecular Players in DNA Methylation in Liver Cancer 4.1 DNA methyltransferases (DNMTs) DNA methyltransferases (DNMTs) are enzymes that catalyze the transfer of methyl groups to cytosine residues within CpG dinucleotides, playing a critical role in the establishment and maintenance of DNA methylation patterns. In hepatocellular carcinoma (HCC), DNMTs such as DNMT1, DNMT3A, and DNMT3B are frequently overexpressed, leading to hypermethylation of tumor suppressor gene promoters, which contributes to tumor progression (Cheng et al., 2021). This hypermethylation silences genes like p16 and RASSF1A, disrupting normal cellular control over the cell cycle and apoptosis, thereby facilitating carcinogenesis. As illustrated in the figure 2, DNMT3A and DNMT3B both contain the PWWP (Pro-Trp-Trp-Pro) domain, the ADD (ATRX-DNMT3A-DNMT3L) domain, and a catalytic domain (CD). The PWWP domain is responsible for binding to H3K36me2/me3, while the ADD domain recognizes H3K4me0, guiding these enzymes to specific chromatin regions for de novo methylation. DNMT3B3, a splice variant of DNMT3B, lacks direct catalytic activity but serves as a regulatory subunit that enhances the methylation activity of DNMT3A and DNMT3B. In contrast, DNMT1 has a more complex structure, including a PIP-box, RFTS domain, CXXC domain, BAH1/2 domains, and a catalytic domain. The RFTS (Replication Foci Targeting Sequence) domain not only recognizes monoubiquitylated PCNA (proliferating cell nuclear antigen) and histone H3 but also acts as an autoinhibitory module through its interaction with the catalytic domain, precisely regulating DNMT1's role in maintaining methylation during cell division (Nishiyama and Nakanishi, 2021). Figure 2 Domain structure of DNA methyltransferase (DNMT) proteins.(Adapted from Nishiyama and Nakanishi, 2021) Image caption: DNMT3A and DNMT3B have three functional domains, a Pro-Trp-Trp-Pro (PWWP) domain, an ATRX-DNMT3A-DNMT3L (ADD) domain, and a catalytic domain (CD); The PWWP domain and ADD domain act as recognition and binding modules for H3K36me2/me3 and H4K4me0, respectively. DNMT3B3, a splicing variant of DNMT3L and DNMT3B, does not show enzymatic activity but promotes de novo methylation as a regulatory subunit of DNMT3A and DNMT3B. DNMT1 is composed of a DMAP1- binding domain, PIP-box, RFTS domain, CXXC domain, BAH1/2 domain, and enzymatic activity domain. The RFTS domain recognizes and binds dual monoubiquitylated PCNA-associated factor 15 (PAF15) or histone H3 for DNMT1 recruitment to DNA methylation sites. The RFTS domain also serves as an autoinhibitory domain via interaction with the CD., Adapted from Nishiyama and Nakanishi, 2021)
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