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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
- Source :
- Hepatology. 66:1413-1429
- Publication Year :
- 2017
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2017.
-
Abstract
- 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 via 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 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 nt -1317/-1167 containing FoxA1 binding element. ChIP assay validated that HBx could enhance the binding property of FoxA1 to MSL2 promoter region. HBx up-regulated MSL2 via activating YAP/FoxA1 signaling. Functionally, silencing MSL2 was able to block the growth of hepatoma cells in vitro and in vivo. In 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 novel insights into the mechanism by which MSL2 as a promotion factor in host cells selectively activates extrachromosomal DNA. This article is protected by copyright. All rights reserved.
- Subjects :
- Hepatocyte Nuclear Factor 3-alpha
0301 basic medicine
Hepatitis B virus
Carcinoma, Hepatocellular
Ubiquitin-Protein Ligases
viruses
Mice, Transgenic
Biology
Virus Replication
medicine.disease_cause
Virus
Minor Histocompatibility Antigens
03 medical and health sciences
Cytidine Deaminase
medicine
Animals
Humans
Gene silencing
Viral Regulatory and Accessory Proteins
Transcription factor
Adaptor Proteins, Signal Transducing
Hepatology
Liver Neoplasms
fungi
Ubiquitination
YAP-Signaling Proteins
Promoter
Hep G2 Cells
cccDNA
Phosphoproteins
Molecular biology
digestive system diseases
Up-Regulation
HBx
030104 developmental biology
Viral replication
Trans-Activators
DNA, Circular
Transcription Factors
Subjects
Details
- ISSN :
- 15273350 and 02709139
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Hepatology
- Accession number :
- edsair.doi.dedup.....180218f6f7c7f16062c04ff942334f4b