Abstract

Background

Hepatitis B virus (HBV) X (HBx) protein is associated with hepatocellular carcinogenesis via the induction of malignant transformation and mitochondrial dysfunction. However, the association between HBx and histone methyltransferase in carcinogenesis has not been fully clarified. In the current study, we analyzed the association between HBx and the histone methyltransferase suppressor of variegation 3–9 homolog 1 (SUV39h1) using HBV replication models.

Methods

We constructed several HBx and SUV39h1 expression plasmids and analyzed the association between HBx and SUV39h1 with respect to HBV replication and hepatocarcinogenesis.

Results

SUV39h1 up-regulation was observed in HBV-infected humanized mouse livers and clinical HBV-related hepatocellular carcinoma tissues, indicating that SUV39h1 expression might be regulated by HBV infection. Through in vitro analysis, we determined that the coactivator domain of HBx interacts with the PSET (PostSET) and SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domains of SUV39h1. The expression levels of 4 genes, activating transcription factor 6, α-fetoprotein, growth arrest and DNA damage–inducible 45a, and dual-specificity phosphatase 1, known to induce carcinogenesis via HBx expression, were up-regulated by HBx and further up-regulated in the presence of both HBx and SUV39h1. Furthermore, histone methyltransferase activity, the main function of SUV39h1, was enhanced in the presence of HBx.

Conclusions

We demonstrated that SUV39h1 and HBx enhance each other’s activity, leading to HBx-mediated hepatocarcinogenesis. We propose that regulation of this interaction could help suppress development of hepatocellular carcinoma.

中文翻译：

---

通过上调SUV39h1信号激活乙型肝炎病毒相关的肝癌发生。

摘要

背景

乙型肝炎病毒（HBV）X（HBx）蛋白通过诱导恶性转化和线粒体功能障碍与肝细胞癌发生有关。但是，HBx和组蛋白甲基转移酶在致癌过程中的关联尚未完全阐明。在当前的研究中，我们使用HBV复制模型分析了HBx与3-9同源1杂色的组蛋白甲基转移酶抑制剂（SUV39h1）之间的关联。

方法

我们构建了几个HBx和SUV39h1表达质粒，并分析了HBx和SUV39h1在HBV复制和肝癌发生方面的关联。

结果

在感染了HBV的人源化小鼠肝脏和临床HBV相关的肝细胞癌组织中观察到SUV39h1的上调，表明SUV39h1的表达可能受HBV感染的调节。通过体外分析，我们确定HBx的共激活域与SUV39h1的PSET（PostSET）和SET（Su（var）3-9，Zestenor-of-zeste，Trithorax）域相互作用。HBx上调了4种基因的表达水平，激活转录因子6，α-甲胎蛋白，生长停滞和DNA损伤诱导型45a，以及双特异性磷酸酶1（已知可通过HBx表达诱导癌变），其表达水平被HBx上调，并进一步上调。在HBx和SUV39h1均存在的情况下进行调节。此外，在HBx存在下，组蛋白甲基转移酶活性（SUV39h1的主要功能）得以增强。

结论

我们证明了SUV39h1和HBx彼此增强活性，导致HBx介导的肝癌发生。我们建议调节这种相互作用可以帮助抑制肝细胞癌的发展。