Curcumin inhibits hepatitis B virus infection by down-regulating cccDNA-bound histone acetylation

doi:10.3748/wjg.v23.i34.6252

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World Journal of Gastroenterology

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World J Gastroenterol. Sep 14, 2017; 23(34): 6252-6260
Published online Sep 14, 2017. doi: 10.3748/wjg.v23.i34.6252

Curcumin inhibits hepatitis B virus infection by down-regulating cccDNA-bound histone acetylation

Zhi-Qiang Wei, Yong-Hong Zhang, Chang-Zheng Ke, Hong-Xia Chen, Pan Ren, Yu-Lin He, Pei Hu, De-Qiang Ma, Jie Luo, Zhong-Ji Meng

Zhi-Qiang Wei, Hong-Xia Chen, Yu-Lin He, Zhong-Ji Meng, Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China

Zhi-Qiang Wei, Chang-Zheng Ke, De-Qiang Ma, Zhong-Ji Meng, Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China

Yong-Hong Zhang, Institute of Wudang Chinese Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China

Pan Ren, Hubei University of Chinese Medicine, Wuhan 430000, Hubei Province, China

Pei Hu, Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan 430000, Hubei Province, China

Jie Luo, Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China

Author contributions: Wei ZQ, Zhang YH and Ke CZ performed the experiments; Meng ZJ and Luo J designed and coordinated the research; Cheng HX and Ma DQ analyzed the data; Wei ZQ and Meng ZJ wrote the paper; Ren P and Hu P reviewed and edited the manuscript; all authors read and approved the manuscript.

Supported by National Natural Science Foundation of China, No. 81541140; Natural Science Foundation of Hubei Province of China, No. 2014CFB645; Research and Development Project of the Science and Technology Plan of Hubei Province, No. 2011BCB030; Foundation for Innovative Research Team of Hubei University of Medicine, No. 2014CXG05; and Key Program for Precision Medicine of Taihe Hospital, No. 2016JZ05.

Conflict-of-interest statement: The authors have no conflicts of interest associated with this manuscript.

Data sharing statement: No additional data are available.

Correspondence to: Zhong-Ji Meng, MD, Professor of Medicine, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan 442000, Hubei Province, China. zhongji.meng@taihehospital.com

Telephone: +86-719-8801821 Fax: +86-719-8801821

Received: June 7, 2017
Peer-review started: June 8, 2017
First decision: July 13, 2017
Revised: July 29, 2017
Accepted: August 15, 2017
Article in press: August 15, 2017
Published online: September 14, 2017
Processing time: 100 Days and 0.6 Hours

Abstract

AIM

To investigate the potential effect of curcumin on hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and the underlying mechanism.

METHODS

A HepG2.2.15 cell line stably transfected with HBV was treated with curcumin, and HBV surface antigen (HBsAg) and e antigen (HBeAg) expression levels were assessed by ELISA. Intracellular HBV DNA replication intermediates and cccDNA were detected by Southern blot and real-time PCR, respectively. The acetylation levels of histones H3 and H4 were measured by Western blot. H3/H4-bound cccDNA was detected by chromatin immunoprecipitation (ChIP) assays. The deacetylase inhibitors trichostatin A and sodium butyrate were used to study the mechanism of action for curcumin. Additionally, short interfering RNAs (siRNAs) targeting HBV were tested along with curcumin.

RESULTS

Curcumin treatment led to time- and dose-dependent reductions in HBsAg and HBeAg expression and significant reductions in intracellular HBV DNA replication intermediates and HBV cccDNA. After treatment with 20 μmol/L curcumin for 2 d, HBsAg and cccDNA levels in HepG2.2.15 cells were reduced by up to 57.7% (P < 0.01) and 75.5% (P < 0.01), respectively, compared with levels in non-treated cells. Meanwhile, time- and dose-dependent reductions in the histone H3 acetylation levels were also detected upon treatment with curcumin, accompanied by reductions in H3- and H4-bound cccDNA. Furthermore, the deacetylase inhibitors trichostatin A and sodium butyrate could block the effects of curcumin. Additionally, transfection of siRNAs targeting HBV enhanced the inhibitory effects of curcumin.

CONCLUSION

Curcumin inhibits HBV gene replication via down-regulation of cccDNA-bound histone acetylation and has the potential to be developed as a cccDNA-targeting antiviral agent for hepatitis B.

Keywords: Curcumin; Hepatitis B virus; Covalently closed circular DNA; Histone deacetylation

Core tip: We showed that curcumin inhibited hepatitis B virus (HBV) replication and expression via reductions in covalently closed circular DNA-bound histone acetylation. Furthermore, siRNAs targeting HBV acted synergistically with curcumin, resulting in enhanced inhibition of HBV.