Hepatitis B virus X protein-elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis.

Yuen Gao, Jinyan Feng, Guang Yang, Shuqin Zhang, Yunxia Liu, Yanan Bu, Mingming Sun, Man Zhao, Fuquan Chen, Weiying Zhang, Lihong Ye, Xiaodong Zhang

Hepatology (Baltimore, Md.) 2017 Nov

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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. 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). © 2017 by the American Association for the Study of Liver Diseases.

Citation

Yuen Gao, Jinyan Feng, Guang Yang, Shuqin Zhang, Yunxia Liu, Yanan Bu, Mingming Sun, Man Zhao, Fuquan Chen, Weiying Zhang, Lihong Ye, Xiaodong Zhang. Hepatitis B virus X protein-elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis. Hepatology (Baltimore, Md.). 2017 Nov;66(5):1413-1429