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

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.

• Authors: 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
• Journal: World journal of gastroenterology (World J Gastroenterol) Vol. 23 Issue 34 Pg. 6252-6260 (Sep 14 2017) ISSN: 2219-2840 [Electronic] United States
• PMID: 28974891 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• DNA, Circular
• DNA, Viral
• Hepatitis B Surface Antigens
• Hepatitis B e Antigens
• Histone Deacetylase Inhibitors
• Histones
• Hydroxamic Acids
• RNA, Small Interfering
• Butyric Acid
• trichostatin A
• E1A-Associated p300 Protein
• EP300 protein, human
• Curcumin

Topics

• Acetylation (drug effects)
• Antiviral Agents (pharmacology)
• Butyric Acid (pharmacology)
• Chromatin Immunoprecipitation
• Curcumin (pharmacology)
• DNA Replication (drug effects)
• DNA, Circular (metabolism)
• DNA, Viral (metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation
• Drug Synergism
• E1A-Associated p300 Protein (antagonists & inhibitors)
• Hep G2 Cells
• Hepatitis B Surface Antigens (drug effects)
• Hepatitis B e Antigens (metabolism)
• Hepatitis B virus (drug effects, genetics)
• Histone Deacetylase Inhibitors (pharmacology)
• Histones (metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• RNA Interference
• RNA, Small Interfering (pharmacology)
• Real-Time Polymerase Chain Reaction