Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 Expression
Histone deacetylase (HDAC) inhibitors show clinical promise for the treatment of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the effect of HDAC inhibitor treatment on hepatitis C virus (HCV) replication in Huh7 human liver cells and in a mouse model of HCV infection. Viral replication was markedly suppressed by the HDAC3 inhibitor at concentrations below 1 mmol/L, with no cellular toxicity. This was accompanied by upregulation of liver-expressed antimicrobial peptide 1(LEAP-1) and downregulation of apolipoprotein-A1 (Apo-A1), as determined by microarray and quantitative RT-PCR analyses. Moreover, HDAC3 was found to modulate the binding of CCAAT-enhancer-binding protein α (C/EBPα), hypoxia-inducible factor 1α (HIF1α), and signal transducer and activator of transcription 3 (STAT3) to the LEAP-1 promoter. HDAC3 inhibitor treatment also blocked HCV replication in a mouse model of HCV infection. These results indicate that epigenetic therapy with HDAC3 inhibitor may be a potential treatment for diseases associated with HCV infection such as HCC.
KeywordsHepatitis C virus (HCV) HDAC3 Apolipoprotein-A1(Apo-A1) LEAP-1 Hepatocellular carcinoma Viral replication
We would like to thank the members of Chen’s lab and the core facilities center of Wuhan institute of virology for technical help. This study was supported by the National Key Research and Development Program of China to YZ (2018YFA0507202) and the Program for Youth Innovation Promotion Association in Chinese Academy of Science to JC.
JC conceived/designed the experiments. YZ and QW performed the experiments and analyzed the data. YQ, JT, XC and DG contributed reagents/materials/analysis tools. JC and XC wrote the manuscript. YZ and QW prepared the figures and tables. JC checked and finalized the manuscript. All authors read and approved the final manuscript.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
Animal and Human Rights Statement
The study was approved by the Animal Ethics Committee of Wuhan Institute of Virology. All institutional and national guidelines for the care and use of laboratory animals were followed.
- Chen J, Wang N, Dong M, Guo M, Zhao Y, Zhuo Z, Zhang C, Chi X, Pan Y, Jiang J, Tang H, Niu J, Yang D, Li Z, Han X, Wang Q, Chen X (2015) The metabolic regulator histone deacetylase 9 contributes to glucose homeostasis abnormality induced by hepatitis C virus infection. Diabetes 64:4088–4098CrossRefGoogle Scholar
- Kato J, Kobune M, Nakamura T, Kuroiwa G, Takada K, Takimoto R, Sato Y, Fujikawa K, Takahashi M, Takayama T, Ikeda T, Niitsu Y (2001) Normalization of elevated hepatic 8-hydroxy-2′-deoxyguanosine levels in chronic hepatitis C patients by phlebotomy and low iron diet. Cancer Res 61:8697–8702PubMedGoogle Scholar
- Mancone C, Steindler C, Santangelo L, Simonte G, Vlassi C, Longo MA, D’Offizi G, Di Giacomo C, Pucillo LP, Amicone L, Tripodi M, Alonzi T (2011) Hepatitis C virus production requires apolipoprotein A-I and affects its association with nascent low-density lipoproteins. Gut 60:378–386CrossRefGoogle Scholar
- Nishina S, Hino K, Korenaga M, Vecchi C, Pietrangelo A, Mizukami Y, Furutani T, Sakai A, Okuda M, Hidaka I, Okita K, Sakaida I (2008) Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 134:226–238CrossRefGoogle Scholar
- Puoti M, Foster GR, Wang S, Mutimer D, Gane E, Moreno C, Chang TT, Lee SS, Marinho R, DuFour JF, Pol S, Hezode C, Gordon SC, Strasser SI, Thuluvath PJ, Zhang Z, Lovell S, Pilot-Matias T, Mensa FJ (2018) High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir: integrated analysis of HCV genotype 1–6 patients without cirrhosis. J Hepatol. https://doi.org/10.1016/j.jhep.2018.03.007 CrossRefPubMedGoogle Scholar
- Sato A, Saito Y, Sugiyama K, Sakasegawa N, Muramatsu T, Fukuda S, Yoneya M, Kimura M, Ebinuma H, Hibi T, Ikeda M, Kato N, Saito H (2013) Suppressive effect of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) on hepatitis C virus replication. J Cell Biochem 114:1987–1996CrossRefGoogle Scholar
- Tovar-Castillo LE, Cancino-Diaz JC, Garcia-Vazquez F, Cancino-Gomez FG, Leon-Dorantes G, Blancas-Gonzalez F, Jimenez-Zamudio L, Garcia-Latorre E, Cancino-Diaz ME (2007) Under-expression of VHL and over-expression of HDAC-1, HIF-1alpha, LL-37, and IAP-2 in affected skin biopsies of patients with psoriasis. Int J Dermatol 46:239–246CrossRefGoogle Scholar
- Vaillancourt FH, Brault M, Pilote L, Uyttersprot N, Gaillard ET, Stoltz JH, Knight BL, Pantages L, McFarland M, Breitfelder S, Chiu TT, Mahrouche L, Faucher AM, Cartier M, Cordingley MG, Bethell RC, Jiang H, White PW, Kukolj G (2012) Evaluation of phosphatidylinositol-4-kinase IIIalpha as a hepatitis C virus drug target. J Virol 86:11595–11607CrossRefGoogle Scholar
- Vassilaki N, Kalliampakou KI, Kotta-Loizou I, Befani C, Liakos P, Simos G, Mentis AF, Kalliaropoulos A, Doumba PP, Smirlis D, Foka P, Bauhofer O, Poenisch M, Windisch MP, Lee ME, Koskinas J, Bartenschlager R, Mavromara P (2013) Low oxygen tension enhances hepatitis C virus replication. J Virol 87:2935–2948CrossRefGoogle Scholar
- World Health Organization Fact sheet, Updated October 2017Google Scholar