Epigenetic silencing of NAD(P)H:quinone oxidoreductase 1 by hepatitis B virus X protein increases mitochondrial injury and cellular susceptibility to oxidative stress in hepatoma cells
Epigenetic silencing of NAD(P)H:quinone oxidoreductase 1 by hepatitis B virus X protein increases mitochondrial injury and cellular susceptibility to oxidative stress in hepatoma cells
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乙型肝炎病毒 X 蛋白对 NAD(P)H:醌氧化还原酶 1 的表观遗传沉默会增加肝癌细胞的线粒体损伤和细胞对氧化应激的敏感性
DOI：
10.1016/j.freeradbiomed.2013.07.037
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发表时间：
2013-12-01
影响因子：
7.4
通讯作者：
Lin, Xu
中科院分区：
文献类型：
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作者：
Wu, Yun-li;Wang, Dong;Lin, Xu
NAD（P）H：醌氧化还原酶1（NQO1）是一种II相酶，参与多巴胺衍生的醌分子和活性氧的解毒。我们先前的工作使用蛋白质组学方法发现，相对于空载体转染的对照组，稳定的产生B型肝炎病毒（HBV）的肝癌细胞中的NQO 1蛋白水平显著降低。然而，NQO1抑制的机制和生物学意义仍然难以捉摸。在这项研究中，我们证明，HBV X蛋白（HBx）诱导的表观遗传沉默的NQO1在肝癌细胞通过启动子高甲基化通过招募DNA甲基转移酶DNMT 3A的启动子区域的NQO1基因。在HBV相关的肝细胞癌（HCC）标本中，HBx表达与NQO1转录呈负相关，但与NQO1启动子高甲基化呈正相关。HBx下调NQO1可降低细胞内谷胱甘肽水平，损害线粒体功能，并增加肝癌细胞对氧化应激诱导的细胞损伤的易感性。这些结果提示了HBV介导的慢性肝病（包括HCC）发病机制的新机制。(C)2013 Elsevier Inc. All rights reserved.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a phase II enzyme that participates in the detoxification of dopamine-derived quinone molecules and reactive oxygen species. Our prior work using a proteomic approach found that NQO1 protein levels were significantly decreased in stable hepatitis B virus (HBV)-producing hepatoma cells relative to the empty-vector-transfected controls. However, the mechanism and biological significance of the NQO1 suppression remain elusive. In this study we demonstrate that HBV X protein (HBx) induces epigenetic silencing of NQO1 in hepatoma cells through promoter hypermethylation via recruitment of DNA methyltransferase DNMT3A to the promoter region of the NQO1 gene. In HBV-related hepatocellular carcinoma (HCC) specimens, HBx expression was correlated negatively to NQO1 transcripts but positively to NQO1 promoter hypermethylation. Downregulation of NQO1 by HBx reduced intracellular glutathione levels, impaired mitochondrial function, and increased susceptibility of hepatoma cells to oxidative stress-induced cell injury. These results suggest a novel mechanism for HBV-mediated pathogenesis of chronic liver diseases, including HCC. (C) 2013 Elsevier Inc. All rights reserved.