Hepatitis B virus X protein-induced aberrant epigenetic modifications contributing to human hepatocellular carcinoma pathogenesis

Abstract

Hepatocellular carcinoma (HCC) remains one of the most prevalent malignant diseases worldwide, and the majority of cases are related to hepatitis B virus (HBV) infection. Interactions between the HBV-encoded X (HBx) protein and host factors are known to play major roles in the onset and progression of HBV-related HCC. These dynamic molecular mechanisms are extremely complex and lead to prominent changes in the host genetic and epigenetic architecture. This review summarizes the current knowledge about HBx-induced epigenetic changes, including aberrations in DNA methylation, histone modifications, and microRNA expression, and their roles in HBV-infected liver cells and HBV-related HCC. Moreover, the HBx-mediated epigenetic control of HBV covalently closed circular DNA (cccDNA) is also discussed. Although this field of study is relatively new, the accumulated evidence has indicated that the epigenetic events induced by HBx play important roles in the development of HBV-related HCC. Ongoing research will help to identify practical applications of the HBV-related epigenetic signatures as biomarkers for early HCC detection or as potential targets to prevent and treat HBV-related HCC.

Fig 1

HBx-induced epigenetic modifications of active and repressed host genes. For genes with tumor-promoting activities, HBx can directly interact with the histone acetyltransferase (HAT) complex, CREB-binding protein (CBP)/P300. HBx-mediated recruitment of the CBP/P300 complex promotes transactivation, resulting in an acetylated (active) histone state of the associated genes. HBx also induces upregulation of the SET and MYND domain-containing 3 (SMYD3) gene, which encodes a histone H3-K4-specific methyltransferase (HMT), resulting in general upregulation of the expression of genes with tumor-promoting activities by increasing H3 lysine 4 methylation. In addition, HBx releases DNMT3A from promoters of cellular genes, resulting in upregulation of the expression of genes with tumor-promoting activities. HBx not only upregulates the expression of genes with tumor-promoting activities but also downregulates the expression of genes with tumor-suppressing activities through its interactions with and manipulation of different types of epigenetic effectors. For genes with tumor-suppressing activity, HBx induces aberrant hypermethylation of CpG islands by upregulating the activity of DNMTs, resulting in and maintaining a nonpermissive heterochromatin state that physically prohibits binding of transcription factors (TF) and polymerase II RNA complexes (Pol II) to the target promoter sequences. HBx can also repress the expression of some genes with tumor-suppressing activities via recruitment of histone deacetylases (HDAC). Hme, histone methylation; M, 5-methylcytosine at CpGs; Ac, histone acetylation.