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Sirtuin 1 Regulates Hepatitis B Virus Transcription and Replication by Targeting Transcription Factor AP-1
Ji-Hua Ren a,
Ying Tao a,f,
Zhen-Zhen Zhang b,
Wei-Xian Chen c,
Xue-Fei Cai a,
Ke Chen a,
Ben C. B. Ko d,
Chun-Li Song a,
Long-Kuan Ran a,
Wan-Yu Li a,
Ai-Long Huang a,e and
Juan Chen a,e
aThe Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
bDepartment of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing, China
cDepartment of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
dDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
eCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Zhejiang, China
fDepartment of Infectious Diseases, The People's Liberation Army 161 Hospital, Wuhan, China
G. McFadden, Editor
- Author Affiliations
ABSTRACT
Chronic hepatitis B virus (HBV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Nevertheless, the molecular mechanism of HBV replication remains elusive. SIRT1 is a class III histone deacetylase that is a structure component of the HBV cccDNA minichromosome. In this study, we found by using microarray-based gene expression profiling analysis that SIRT1 was upregulated in HBV-expressing cells. Gene silencing of SIRT1 significantly inhibited HBV DNA replicative intermediates, 3.5-kb mRNA, and core protein levels. In contrast, the overexpression of SIRT1 augmented HBV replication. Furthermore, SIRT1 enhanced the activity of HBV core promoter by targeting transcription factor AP-1. The c-Jun subunit of AP-1 was bound to the HBV core promoter region, as demonstrated by using a chromatin immunoprecipitation assay. Mutation of AP-1 binding site or knockdown of AP-1 abolished the effect of SIRT1 on HBV replication. Finally, SIRT1 inhibitor sirtinol also suppressed the HBV DNA replicative intermediate, as well as 3.5-kb mRNA. Our study identified a novel host factor, SIRT1, which may facilitate HBV replication in hepatocytes. These data suggest a rationale for the use of SIRT1 inhibitor in the treatment of HBV infection.
FOOTNOTES
Received 2 October 2013.
Accepted 5 December 2013.
Address correspondence to Juan Chen, [email protected], or Ailong Huang, [email protected].
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