Deregulation of Epigenetic Mechanisms by the Hepatitis B Virus X Protein in Hepatocarcinogenesis

Ourania Andrisani

doi:10.3390/v5030858

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.

Highlights

Chronic hepatitis B virus (HBV) infection is a major etiologic factor in pathogenesis of hepatocellular carcinoma (HCC) [1,2]
Given that classification of tumors by histologic markers does not identify the cellular origin of the tumor, i.e., differentiated vs. progenitor cell, in this review I explore mechanisms that could mediate the upregulated expression of the hepatoblast/fetal markers and imprinted genes observed in the G1 subgroup of HBV-mediated HCCs
Since HBV infection occurs in differentiated hepatocytes, requiring the transcriptional activity of hepatocyte-specific transcription factors [97], it is intriguing that subgroups of HBV-induced HCCs express hepatoblast and fetal markers

Summary

Introduction

Chronic hepatitis B virus (HBV) infection is a major etiologic factor in pathogenesis of hepatocellular carcinoma (HCC) [1,2]. Global transcriptome analyses of human liver tumors have identified distinct subgroups of HCCs associated with specific genetic changes and clinical prognosis [6]. Of special interest is the HCC subgroup G1, identified and characterized by the transcriptome studies of Boyault et al [7]. The G1 subgroup is associated with low titer HBV infection, high rate of chromosomal instability, poor prognosis, and high expression levels of AFP (alpha-fetoprotein), imprinted genes (IGFII, H19, PEG3 and PEG10), and transcription factor SOX9, a key regulator of pancreatobiliary ductal system development. Given that classification of tumors by histologic markers does not identify the cellular origin of the tumor, i.e., differentiated vs progenitor cell, in this review I explore mechanisms that could mediate the upregulated expression of the hepatoblast/fetal markers and imprinted genes observed in the G1 subgroup of HBV-mediated HCCs

The HBV Life Cycle

Suz12 Containing PRC2 Complex

Regulation of the PRC2 Complex

DNA Methylation and the X Protein

Findings

Conclusion