Induction of HOX Genes by Hepatitis C Virus Infection via Impairment of Histone H2A Monoubiquitination
Induction of HOX Genes by Hepatitis C Virus Infection via Impairment of Histone H2A Monoubiquitination
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DOI：
10.1128/jvi.01784-20
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发表时间：
2020-12
影响因子：
5.4
通讯作者：
Hirotake Kasai;K. Mochizuki;Tomohisa Tanaka;A. Yamashita;Y. Matsuura;K. Moriishi
中科院分区：
文献类型：
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作者：
Hirotake Kasai;K. Mochizuki;Tomohisa Tanaka;A. Yamashita;Y. Matsuura;K. Moriishi
最近，在大多数丙型肝炎患者中，直接作用抗病毒(DAA)治疗可以实现持续的病毒学应答。不幸的是，DAA治疗并不能完全消除患肝细胞癌的风险。摘要丙型肝炎病毒感染可引起包括肝细胞癌在内的多种肝脏病变。同源盒(Homeobox，HOX)基因产物调控胚胎发育，与肿瘤发生有关，但目前对HOX基因的调控尚不清楚。我们检测了丙型肝炎病毒感染对HOX基因表达的影响。在本研究中，丙型肝炎病毒感染诱导了超过一半的HOX基因，并降低了抑制HOX基因启动子活性的赖氨酸119(K119)上的组蛋白H_2A单素化水平(H_2Aub)。丙型肝炎病毒感染也促进了RNF2的蛋白酶体依赖的降解，RNF2是一种E3连接酶，作为多梳抑制复合体1的一部分，介导了H_2A的单素化。由于全基因组复制子细胞而不是亚基因组复制子细胞表现出RNF2和H_2Aub水平的降低和HOX基因的诱导，我们重点关注核心蛋白。核心蛋白的表达减少了RNF2和H2Aub的数量，并诱导了Hox基因的表达。LY-411575可通过抑制信号肽酶降低丙型肝炎病毒核心蛋白的表达，而不影响其他病毒蛋白的表达，并呈剂量依赖性地恢复丙型肝炎病毒感染细胞中RNF2和H_2Aub的含量，并损害HOX基因的诱导和病毒颗粒的产生，但不影响病毒复制。染色质免疫沉淀分析结果还表明，位于HOX基因启动子的H_2Aub的减少依赖于感染和蛋白酶体。这些结果表明，丙型肝炎病毒感染或核心蛋白通过降低RNF2水平来损害组蛋白H2A的单泛素化，从而诱导HOX基因的表达。在大多数丙型肝炎患者中，近期持续的病毒学应答可以通过直接作用抗病毒(DAA)治疗来实现。不幸的是，DAA治疗并不能完全消除患肝细胞癌的风险。一些表观遗传因素，包括组蛋白修饰，众所周知有助于丙型肝炎病毒(HCV)相关的肝细胞癌。然而，丙型肝炎病毒感染对组蛋白修饰的调节还没有被详细阐明。在这项研究中，我们的数据表明，丙型肝炎病毒感染或丙型肝炎病毒核心蛋白表达通过RNF2失稳损害同源盒(Homeobox，HOX)基因启动子中组蛋白H 2A K119的单核苷酸活化，进而诱导HOX基因。一些证据表明，在某些类型的肿瘤中，几个HOX基因的表达是失调的。这些发现揭示了丙型肝炎病毒相关组蛋白修饰的新机制，并可能为肝癌的诊断和预防提供新的靶点。
Recently sustained virologic response can be achieved by direct-acting antiviral (DAA) therapy in most hepatitis C patients. Unfortunately, DAA therapy does not completely eliminate a risk of hepatocellular carcinoma (HCC). ABSTRACT Hepatitis C virus (HCV) infection causes liver pathologies, including hepatocellular carcinoma (HCC). Homeobox (HOX) gene products regulate embryonic development and are associated with tumorigenesis, although the regulation of HOX genes by HCV infection has not been clarified in detail. We examined the effect of HCV infection on HOX gene expression. In this study, HCV infection induced more than half of the HOX genes and reduced the level of histone H2A monoubiquitination on lysine 119 (K119) (H2Aub), which represses HOX gene promoter activity. HCV infection also promoted proteasome-dependent degradation of RNF2, which is an E3 ligase mediating H2A monoubiquitination as a component of polycomb repressive complex 1. Since full-genomic replicon cells but not subgenomic replicon cells exhibited reduced RNF2 and H2Aub levels and induction of HOX genes, we focused on the core protein. Expression of the core protein reduced the amounts of RNF2 and H2Aub and induced HOX genes. Treatment with LY-411575, which can reduce HCV core protein expression via signal peptide peptidase (SPP) inhibition without affecting other viral proteins, dose-dependently restored the amounts of RNF2 and H2Aub in HCV-infected cells and impaired the induction of HOX genes and production of viral particles but not viral replication. The chromatin immunoprecipitation assay results also indicated infection- and proteasome-dependent reductions in H2Aub located in HOX gene promoters. These results suggest that HCV infection or core protein induces HOX genes by impairing histone H2A monoubiquitination via a reduction in the RNF2 level. IMPORTANCE Recently sustained virologic response can be achieved by direct-acting antiviral (DAA) therapy in most hepatitis C patients. Unfortunately, DAA therapy does not completely eliminate a risk of hepatocellular carcinoma (HCC). Several epigenetic factors, including histone modifications, are well known to contribute to hepatitis C virus (HCV)-associated HCC. However, the regulation of histone modifications by HCV infection has not been clarified in detail. In this study, our data suggest that HCV infection or HCV core protein expression impairs monoubiquitination of histone H2A K119 in the homeobox (HOX) gene promoter via destabilization of RNF2 and then induces HOX genes. Several lines of evidence suggest that the expression of several HOX genes is dysregulated in certain types of tumors. These findings reveal a novel mechanism of HCV-related histone modification and may provide information about new targets for diagnosis and prevention of HCC occurrence.