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Virologica Sinica

, Volume 33, Issue 5, pp 418–428 | Cite as

Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 Expression

  • Yuan Zhou
  • Qian Wang
  • Qi Yang
  • Jielin Tang
  • Chonghui Xu
  • Dongwei Gai
  • Xinwen Chen
  • Jizheng Chen
Research Article

Abstract

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.

Keywords

Hepatitis C virus (HCV) HDAC3 Apolipoprotein-A1(Apo-A1) LEAP-1 Hepatocellular carcinoma Viral replication 

Notes

Acknowledgements

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.

Author Contributions

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.

Supplementary material

12250_2018_57_MOESM1_ESM.pdf (627 kb)
Supplementary material 1 (PDF 628 kb)
12250_2018_57_MOESM2_ESM.xlsx (115 kb)
Supplementary material 2 (XLSX 115 kb)

References

  1. Ai T, Xu Y, Qiu L, Geraghty RJ, Chen L (2015) Hydroxamic acids block replication of hepatitis C virus. J Med Chem 58:785–800CrossRefGoogle Scholar
  2. Aoki H, Hayashi J, Moriyama M, Arakawa Y, Hino O (2000) Hepatitis C virus core protein interacts with 14-3-3 protein and activates the kinase Raf-1. J Virol 74:1736–1741CrossRefGoogle Scholar
  3. Berthiaume M, Boufaied N, Moisan A, Gaudreau L (2006) High levels of oxidative stress globally inhibit gene transcription and histone acetylation. DNA Cell Biol 25:124–134CrossRefGoogle Scholar
  4. Bird A (2007) Perceptions of epigenetics. Nature 447:396–398CrossRefGoogle Scholar
  5. Bugianesi E, Salamone F, Negro F (2012) The interaction of metabolic factors with HCV infection: does it matter? J Hepatol 56(Suppl 1):S56–S65CrossRefGoogle Scholar
  6. Chen J, Zhao Y, Zhang C, Chen H, Feng J, Chi X, Pan Y, Du J, Guo M, Cao H, Wang Z, Pei R, Wang Q, Pan L, Niu J, Chen X, Tang H (2014) Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice. Cell Res 24:1050–1066CrossRefGoogle Scholar
  7. 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
  8. Gottwein JM, Pham LV, Mikkelsen LS, Ghanem L, Ramirez S, Scheel TKH, Carlsen THR, Bukh J (2018) Efficacy of NS5A inhibitors against hepatitis C virus genotypes 1–7 and escape variants. Gastroenterology 154:1435–1448CrossRefGoogle Scholar
  9. Guo M, Pei R, Yang Q, Cao H, Wang Y, Wu C, Chen J, Zhou Y, Hu X, Lu M, Chen X (2015) Phosphatidylserine-specific phospholipase A1 involved in hepatitis C virus assembly through NS2 complex formation. J Virol 89:2367–2377CrossRefGoogle Scholar
  10. Heo YA, Deeks ED (2018) Sofosbuvir/velpatasvir/voxilaprevir: a review in chronic hepatitis C. Drugs 78:577–587CrossRefGoogle Scholar
  11. Ivanov AV, Smirnova OA, Ivanova ON, Masalova OV, Kochetkov SN, Isaguliants MG (2011) Hepatitis C virus proteins activate NRF2/ARE pathway by distinct ROS-dependent and independent mechanisms in HUH7 cells. PLoS ONE 6:e24957CrossRefGoogle Scholar
  12. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P (2005) Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309:1577–1581CrossRefGoogle Scholar
  13. 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
  14. Kawamura Y, Akuta N, Sezaki H, Hosaka T, Someya T, Kobayashi M, Suzuki F, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kumada H (2005) Determinants of serum ALT normalization after phlebotomy in patients with chronic hepatitis C infection. J Gastroenterol 40:901–906CrossRefGoogle Scholar
  15. Ke Q, Costa M (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70:1469–1480CrossRefGoogle Scholar
  16. Lu YS, Kashida Y, Kulp SK, Wang YC, Wang D, Hung JH, Tang M, Lin ZZ, Chen TJ, Cheng AL, Chen CS (2007) Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma. Hepatology 46:1119–1130CrossRefGoogle Scholar
  17. Lyberopoulou A, Chachami G, Gatselis NK, Kyratzopoulou E, Saitis A, Gabeta S, Eliades P, Paraskeva E, Zachou K, Koukoulis GK, Mamalaki A, Dalekos GN, Simos G (2015) Low serum hepcidin in patients with autoimmune liver diseases. PLoS ONE 10:e0135486CrossRefGoogle Scholar
  18. 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
  19. Mifuji R, Kobayashi Y, Ma N, Qiang QL, Urawa N, Horiike S, Iwasa M, Kaito M, Malavasi F, Adachi Y (2006) Role of transferrin receptor 2 in hepatic accumulation of iron in patients with chronic hepatitis C. J Gastroenterol Hepatol 21:144–151CrossRefGoogle Scholar
  20. Minichini C, Starace M, De Pascalis S, Macera M, Occhiello L, Caroprese M, Vitrone M, Iovinella V, Guerrera B, Masarone M, Coppola N (2018) HCV-genotype 3 h, a difficult-to-diagnose sub-genotype in the DAA era. Antivir Ther.  https://doi.org/10.3851/IMP3228 CrossRefPubMedGoogle Scholar
  21. Miura K, Taura K, Kodama Y, Schnabl B, Brenner DA (2008) Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 48:1420–1429CrossRefGoogle Scholar
  22. 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
  23. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS (2007) Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 117:1926–1932CrossRefGoogle Scholar
  24. Pietrangelo A, Dierssen U, Valli L, Garuti C, Rump A, Corradini E, Ernst M, Klein C, Trautwein C (2007) STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology 132:294–300CrossRefGoogle Scholar
  25. 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
  26. 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
  27. Schumacker PT (2005) Hypoxia-inducible factor-1 (HIF-1). Crit Care Med 33:S423–S425CrossRefGoogle Scholar
  28. Sengupta N, Seto E (2004) Regulation of histone deacetylase activities. J Cell Biochem 93:57–67CrossRefGoogle Scholar
  29. Shu XS, Li L, Tao Q (2012) Chromatin regulators with tumor suppressor properties and their alterations in human cancers. Epigenomics 4:537–549CrossRefGoogle Scholar
  30. Su X, Liu S, Zhang X, Lam SM, Hu X, Zhou Y, Chen J, Wang Y, Wu C, Shui G, Lu M, Pei R, Chen X (2017) Requirement of cytosolic phospholipase A2 gamma in lipid droplet formation. Biochim Biophys Acta 1862:692–705CrossRefGoogle Scholar
  31. Sun Z, Miller RA, Patel RT, Chen J, Dhir R, Wang H, Zhang D, Graham MJ, Unterman TG, Shulman GI, Sztalryd C, Bennett MJ, Ahima RS, Birnbaum MJ, Lazar MA (2012) Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med 18:934–942CrossRefGoogle Scholar
  32. 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
  33. 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
  34. 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
  35. Vecchi C, Montosi G, Zhang K, Lamberti I, Duncan SA, Kaufman RJ, Pietrangelo A (2009) ER stress controls iron metabolism through induction of hepcidin. Science 325:877–880CrossRefGoogle Scholar
  36. World Health Organization Fact sheet, Updated October 2017Google Scholar
  37. Xu S, Pei R, Guo M, Han Q, Lai J, Wang Y, Wu C, Zhou Y, Lu M, Chen X (2012) Cytosolic phospholipase A2 gamma is involved in hepatitis C virus replication and assembly. J Virol 86:13025–13037CrossRefGoogle Scholar
  38. Yang XJ, Gregoire S (2005) Class II histone deacetylases: from sequence to function, regulation, and clinical implication. Mol Cell Biol 25:2873–2884CrossRefGoogle Scholar
  39. Yuan ZL, Guan YJ, Chatterjee D, Chin YE (2005) Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307:269–273CrossRefGoogle Scholar
  40. Zhai N, Li H, Song H, Yang Y, Cui A, Li T, Niu J, Crispe IN, Su L, Tu Z (2017) Hepatitis C virus induces MDSCs-like monocytes through TLR2/PI3K/AKT/STAT3 signaling. PLoS ONE 12:e0170516CrossRefGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.State Key Laboratory of VirologyWuhan Institute of Virology, Chinese Academy of SciencesWuhanChina
  2. 2.University of Chinese Academy of SciencesBeijingChina
  3. 3.Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjingChina

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