[75] As summarized in Table 1, several specific miRNA have been reported to be directly regulated from their own promoters by epigenetic alterations in HCC.[76, 77] These findings indicate that specific miRNA including miR-1, miR-124 and miR-203 are PARP inhibitor tumor-suppressor miRNA that inhibit their
target oncogenes and are epigenetically silenced during hepatocarcinogenesis. Reactivation of these miRNA by chromatin-modifying drugs such as DNA methylation inhibitor and HDAC inhibitor may be a novel therapeutic strategy for HCC. RECENT STUDIES HAVE reported that some miRNA can regulate the key chromatin-modifying factors for DNA methylation and histone modifications such as DNMT1, DNMT3A, DNMT3B and EZH2 as their targets, suggesting that these miRNA have important roles in the epigenetic control of gene expression (Table 2).[78] Olaparib in vitro It has been
shown that miR-152 is downregulated in HCC and targets DNMT1.[79] miR-152 may act as a tumor suppressor via suppression of DNMT1 and it can be a new target for epigenetic therapy of HCC. PRC1 and PRC2-mediated epigenetic regulation is critical for maintaining cellular homeostasis. PRC2 mediates epigenetic gene silencing by tri-methylating histone H3 lysine 27 (H3K27me3) and is known to aberrantly silence tumor suppressor genes in cancer. EZH2, the catalytic subunit of PRC2, enhances tumorigenesis and is commonly overexpressed in several types of cancer. miR-101 is downregulated in bladder cancer, and miR-101 directly represses EZH2. This suggests that abnormal downregulation of miR-101 could lead to the overexpression of EZH2 frequently MCE seen in cancer. miR-101 may be a potent tumor suppressor by altering global chromatin structure through repression of EZH2.[80, 81] The CCCTC-binding factor, CTCF, is known to bind insulators and exhibits an enhancer-blocking and barrier function, and more recently, it also
contributes to the 3-D organization of the genome. CTCF can also serve as a barrier against the spread of DNA methylation and histone repressive marks over promoter regions of tumor suppressor genes. Recent studies have shown that CTCF is also involved in the regulation of miRNA in cancer cells and stem cells.[82] Watanabe et al.[83] have reported that CTCF plays important roles in the regulation of the cytokine genes TNF and LT in HCC cells. Figure 3 shows a model summarizing the cross-talk between epigenetics and miRNA and the link between miRNA and regulated genes. In normal hepatocytes, miR-152 is substantially expressed, and its target gene DNMT1 is suppressed. On the other hand, miR-152 is downregulated in HCC cells, resulting in overexpression of DNMT1 accompanied by aberrant DNA methylation of some tumor suppressor miRNA such as miR-1 and miR-124. Downregulation of miR-1 and miR-124 cause activation of their target oncogenes. Thus, epigenetics and miRNA are affected by each other and their cross-talk may play critical roles in the hepatocarcinogenesis.