Gene Regulation
The X Protein of Hepatitis B Virus Inhibits Apoptosis in Hepatoma Cells through Enhancing the Methionine Adenosyltransferase 2A Gene Expression and Reducing S-Adenosylmethionine Production*

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The X protein (HBx) of hepatitis B virus (HBV) is involved in the development of hepatocellular carcinoma (HCC), and methionine adenosyltransferase 2A (MAT2A) promotes the growth of liver cancer cells through altering S-adenosylmethionine homeostasis. Thus, we speculated that a link between HBx and MAT2A may contribute to HCC development. In this study, the effects of HBx on MAT2A expression and cell apoptosis were investigated, and the molecular mechanism by which HBx and MAT2A regulate tumorigenesis was evaluated. Results from immunohistochemistry analyses of 37 pairs of HBV-associated liver cancer tissues/corresponding peritumor tissues showed that HBx and MAT2A are highly expressed in most liver tumor tissues. Our in vitro results revealed that HBx activates MAT2A expression in a dose-dependent manner in hepatoma cells, and such regulation requires the cis-regulatory elements NFB and CREB on the MAT2A gene promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) further demonstrated that HBx facilitates the binding of NFB and CREB to MAT2A gene promoter. In addition, overexpression of HBx or MAT2A inhibits cell apoptosis, whereas knockdown of MAT2A expression stimulates apoptosis in hepatoma cells. Furthermore, we demonstrated that HBx reduces MAT1A expression and AdoMet production but enhances MAT2β expression. Thus, we proposed that HBx activates MAT2A expression through NFB and CREB signaling pathways to reduce AdoMet production, inhibit hepatoma cell apoptosis, and perhaps enhance HCC development. These findings should provide new insights into our understanding how the molecular mechanisms underline the effects of HBV infection on the production of MAT2A and the development of HCC.

Apoptosis
Cancer Tumor Promoter
Chromatin Immunoprecipitation (ChiP)
CREB
DNA-Protein Interaction
DNA Viruses
Gene Regulation
Hepatitis Virus
Oncogene
S-Adenosylmethionine (AdoMet)

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This work was supported by National Mega Project on Major Infectious Diseases Prevention and Treatment Research Grants 2008ZX10002-009 and 2009ZX10004-207, National Mega Project on Major Drug Development Research Grants 2009ZX09301-014 and 2011ZX09401-302, Major State Basic Research Development Program of China Research Grant 2005CB522901, National Science Foundation of China Research Grants 30730001 and 30872491, Program for Changjiang Scholars and Innovative Research Team in University Research Grant IRT0745, Key Project of Chinese Ministry of Education Research Grant 204114208, Department of Science and Technology of Hubei Province Research Grant 2005ABC003, Fundamental Research Funds for the Central Universities Research Grant 1102001, and Specialized Research Fund for the Doctoral Program of Higher Education Research Grant 20090141110033.