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Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. Despite the availability of a HBV vaccine, current treatments for HCC are inadequate. Globally, 257 million people are chronic HBV carriers, and children born from HBV-infected mothers become chronic carriers, destined to develop liver cancer. Thus, new therapeutic approaches are needed to target essential pathways involved in HCC pathogenesis. Accumulating evidence supports existence of hepatic cancer stem cells (hCSCs), which contribute to chemotherapy resistance and cancer recurrence after treatment or surgery. Understanding how hCSCs form will enable development of therapeutic strategies to prevent their formation. Recent studies have identified an epigenetic mechanism involving the downregulation of the chromatin modifying Polycomb Repressive Complex 2 (PRC2) during HBV infection, which results in re-expression of hCSC marker genes in infected hepatocytes and HBV-associated liver tumors. However, the genesis of hCSCs requires, in addition to the expression of hCSC markers cellular changes, rewiring of metabolism, cell survival, escape from programmed cell death, and immune evasion. How these changes occur in chronically HBV-infected hepatocytes is not yet understood. In this review, we will present the basics about HBV infection and hepatocarcinogenesis. Next, we will discuss studies describing the mutational landscape of liver cancers and how epigenetic mechanisms likely orchestrate cellular reprograming of hepatocytes to enable formation of hCSCs. [ABSTRACT FROM AUTHOR]

This review focuses on the significance of deregulation of epigenetic mechanisms by the hepatitis B virus (HBV) X protein in hepatocarcinogenesis and HBV replication. Epigenetic mechanisms, DNA methylation, and specific histone modifications, e.g., trimethylation of H3 on lysine-27 or lysine-4, maintain 'cellular memory' by silencing expression of lineage-inducing factors in stem cells and conversely, of pluripotency factors in differentiated cells. The X protein has been reported to induce expression of DNA methyltransferases (DNMTs), likely promoting epigenetic changes during hepatocarcinogenesis. Furthermore, in cellular and animal models of X-mediated oncogenic transformation, protein levels of chromatin modifying proteins Suz12 and Znf198 are down-regulated. Suz12 is essential for the Polycomb Repressive Complex 2 (PRC2) mediating the repressive trimethylation of H3 on lysine-27 (H3K27me3). Znf198, stabilizes the LSD1-CoREST-HDAC complex that removes, via lysine demethylase1 (LSD1), the activating trimethylation of H3 on lysine-4 (H3K4me3). Down-regulation of Suz12 also occurs in liver tumors of woodchucks chronically infected by woodchuck hepatitis virus, an animal model recapitulating HBV-mediated hepatocarcinogenesis in humans. Significantly, subgroups of HBV-induced liver cancer re-express hepatoblast and fetal markers, and imprinted genes, suggesting hepatocyte reprogramming during oncogenic transformation. Lastly, down-regulation of Suz12 and Znf198 enhances HBV replication. Collectively, these observations suggest deregulation of epigenetic mechanisms by HBV X protein influences both the viral cycle and the host cell. [ABSTRACT FROM AUTHOR]