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

• Published in: World journal of gastroenterology : WJG 2017-09, Vol.23 (34), p.6252-6260
• Main Authors: Wei, Zhi-Qiang, Zhang, Yong-Hong, Ke, Chang-Zheng, Chen, Hong-Xia, Ren, Pan, He, Yu-Lin, Hu, Pei, Ma, De-Qiang, Luo, Jie, Meng, Zhong-Ji
• Format: Article
• Language: English
• Subjects: Acetylation - drug effects; Antiviral Agents - pharmacology; Basic Study; 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 e Antigens - metabolism; Hepatitis B Surface Antigens - drug effects; Hepatitis B virus - drug effects; Hepatitis B virus - genetics; Histone Deacetylase Inhibitors - pharmacology; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; Real-Time Polymerase Chain Reaction; RNA Interference; RNA, Small Interfering - pharmacology
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v23.i34.6252

To investigate the potential effect of curcumin on hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and the underlying mechanism. 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. 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% ( < 0.01) and 75.5% ( < 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. Curcumin inhibits HBV gene replication down-regulation of cccDNA-bound histone acetylation and has the potential to be developed as a cccDNA-targeting antiviral agent for hepatitis B.