State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China.
Virol Sin. 2018 Oct;33(5):418-428. doi: 10.1007/s12250-018-0057-7. Epub 2018 Oct 17.
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.
组蛋白去乙酰化酶 (HDAC) 抑制剂在治疗癌症方面具有临床应用前景，包括肝细胞癌 (HCC)。在这项研究中，我们研究了 HDAC 抑制剂治疗对 Huh7 人肝癌细胞和 HCV 感染小鼠模型中 HCV 复制的影响。HDAC3 抑制剂在低于 1mmol/L 的浓度下即可显著抑制病毒复制，且无细胞毒性。这伴随着肝表达的抗菌肽 1（LEAP-1）的上调和载脂蛋白-A1（Apo-A1）的下调，通过微阵列和定量 RT-PCR 分析确定。此外，发现 HDAC3 调节 CCAAT 增强子结合蛋白 α (C/EBPα)、缺氧诱导因子 1α (HIF1α) 和信号转导和转录激活因子 3 (STAT3) 与 LEAP-1 启动子的结合。HDAC3 抑制剂治疗也阻断了 HCV 感染小鼠模型中的 HCV 复制。这些结果表明，HDAC3 抑制剂的表观遗传治疗可能是治疗与 HCV 感染相关疾病（如 HCC）的一种潜在方法。
