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

doi:10.1007/s12250-018-0057-7

October 2018

Yuan Zhou, Qian Wang, Qi Yang, Jielin Tang, Chonghui Xu, Dongwei Gai, Xinwen Chen and Jizheng Chen. Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 Expression[J]. Virologica Sinica, 2018, 33(5): 418-428. doi: 10.1007/s12250-018-0057-7

Citation: Yuan Zhou, Qian Wang, Qi Yang, Jielin Tang, Chonghui Xu, Dongwei Gai, Xinwen Chen, Jizheng Chen. Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 Expression .VIROLOGICA SINICA, 2018, 33(5) : 418-428. http://dx.doi.org/10.1007/s12250-018-0057-7

组蛋白去乙酰化酶3抑制剂通过调控Apo-A1和LEAP-1表达抑制丙型肝炎病毒复制

周缘 ^1, ,
王倩 ^3, ,
杨琪 ^1,2 ,
唐婕琳 ^1,2 ,
许崇辉 ^1,2 ,
盖冬玮 ^1,2 ,
陈新文 ¹ ,
陈继征 ^1,,

1.
中国科学院武汉病毒研究所

通讯作者： 陈继征, chenjz@wh.iov.cn
收稿日期： 2018-07-27
录用日期： 2018-08-24
出版日期： 2018-10-17

摘要

组蛋白去乙酰化酶（HDAC）抑制剂在临床上用于治疗癌症如肝癌。在本研究中，我们研究了HDAC抑制剂在细胞水平及动物水平对丙型肝炎病毒(HCV)复制的影响。在浓度低于1 mmol/L时，HDAC3抑制剂显著抑制HCV复制且没有细胞毒性。通过基因芯片和荧光定量PCR分析，HDAC3抑制剂会导致HCV负相关蛋白肝脏抗菌肽1(LEAP-1)上调，正相关蛋白载脂蛋白a1 (Apo-A1)下调，从而抑制HCV复制。进一步的机制研究显示，HDAC3通过调节 C / EBPα，低氧诱导因子1α(HIF1α)和信号传感器和转录激活3(STAT3)的乙酰化修饰影响它们的LEAP-1启动子的结合能力。HDAC3抑制剂证明在HCV小鼠模型也有治疗效果。这些结果表明，HDAC3抑制剂可能是HCV感染相关疾病(如HCC)的一种潜在治疗方法。

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

Yuan Zhou ^1, ,
Qian Wang ^3, ,
Qi Yang ^1,2 ,
Jielin Tang ^1,2 ,
Chonghui Xu ^1,2 ,
Dongwei Gai ^1,2 ,
Xinwen Chen ¹ ,
Jizheng Chen ^1,,

1.
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
2.
University of Chinese Academy of Sciences, Beijing 100101, China
3.
Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, China

Corresponding author: Jizheng Chen, chenjz@wh.iov.cn
Received Date: 27 July 2018
Accepted Date: 24 August 2018
Published Date: 17 October 2018

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.

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