Abstract
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.
Keywords
Hepatitis B virus (HBV); HBV X protein; Hepatocellular Carcinoma (HCC); HBV replication; epigenetic regulation; DNA methylation; DNA methyl transferases (DNMTs); Polycomb Repressive complex 2 (PRC2); Suz12; suppressor of zeste 12 homolog (Drosophila); Znf198; zinc finger; MYM-type 2; LSD1-Co-REST-HDAC1
Date of this Version
3-18-2013
Recommended Citation
Andrisani, O.M. Deregulation of Epigenetic Mechanisms by the Hepatitis B Virus X Protein in Hepatocarcinogenesis. Viruses 2013, 5, 858-872.
Comments
This is a PDF of Andrisani, O.M. Deregulation of Epigenetic Mechanisms by the Hepatitis B Virus X Protein in Hepatocarcinogenesis. Viruses 2013, 5, 858-872. DOI: 10.3390/v5030858, published by MDPI AG, Basel, Switzerland. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).