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Hepatitis B virus X protein–elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis
Yuen Gao1,†, Jinyan Feng1,†, Guang Yang1, Shuqin Zhang1, Yunxia Liu1, Yanan Bu1, Mingming Sun1, Man Zhao1, Fuquan Chen1, Weiying Zhang1, Lihong Ye2,* andXiaodong Zhang1,*
Version of Record online: 11 OCT 2017
DOI: 10.1002/hep.29316
© 2017 by the American Association for the Study of Liver Diseases.
Issue
Hepatology
Volume 66, Issue 5, pages 1413–1429, November 2017
Article has an altmetric score of 1
1 State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China
2 State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, China
† These authors contributed equally to this work.
Email: Lihong Ye ([email protected]), Xiaodong Zhang ([email protected])
*ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Xiaodong Zhang, M.D., Ph.D.
Nankai University
94 Weijin Road
Tianjin 300071
P. R. China
E-mail: [email protected]
or
Lihong Ye, M.D., Ph.D.
Nankai University
94 Weijin Road
Tianjin 300071
P. R. China
E-mail: [email protected]
Potential conflict of interest: Nothing to report.
Supported in part by the National Basic Research Program of China (973 Program, grant nos. 2015CB553703 and 2015CB553905), the National Natural Science Foundation of China (grant nos. 31670769 and 31470756), and the Project of Prevention and Treatment of Key Infectious Diseases (grant no. 2014ZX0002002-005).
Chronic hepatitis B virus (HBV) infection is a leading cause in the occurrence of hepatitis B, liver cirrhosis, and liver cancer, in which nuclear HBV covalently closed circular DNA (cccDNA), the genomic form that templates viral transcription and sustains viral persistence, plays crucial roles. In the present study, we explored the hypothesis that HBV X protein (HBx)-elevated male-specific lethal 2 (MSL2) activated HBV replication by modulating cccDNA in hepatoma cells, leading to hepatocarcinogenesis. Immunohistochemical analysis revealed that the expression of MSL2 was positively associated with that of HBV and was increased in the liver tissues of HBV-transgenic mice and clinical HCC patients. Interestingly, microarray profiling identified that MSL2 was associated with those genes responding to the virus. Mechanistically, MSL2 could maintain HBV cccDNA stability through degradation of APOBEC3B by ubiquitylation in hepatoma cells. Above all, HBx accounted for the up-regulation of MSL2 in stably HBx-transfected hepatoma cell lines and liver tissues of HBx-transgenic mice. Luciferase reporter gene assays revealed that the promoter region of MSL2 regulated by HBx was located at nucleotide −1317/−1167 containing FoxA1 binding element. Chromatin immunoprecipitation assay validated that HBx could enhance the binding property of FoxA1 to MSL2 promoter region. HBx up-regulated MSL2 by activating YAP/FoxA1 signaling. Functionally, silencing MSL2 was able to block the growth of hepatoma cells in vitro and in vivo. Conclusion: HBx-elevated MSL2 modulates HBV cccDNA in hepatoma cells to promote hepatocarcinogenesis, forming a positive feedback loop of HBx/MSL2/cccDNA/HBV. Our finding uncovers insights into the mechanism by which MSL2 as a promotion factor in host cells selectively activates extrachromosomal DNA. (Hepatology 2017;66:1413–1429).
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