HBx increases chromatin accessibility and ETV4 expression to regulate dishevelled-2 and promote HCC progression.
HBx increases chromatin accessibility and ETV4 expression to regulate dishevelled-2 and promote HCC progression.
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DOI：
10.1038/s41419-022-04563-9
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发表时间：
2022-02-04
影响因子：
9
通讯作者：
Fan H
中科院分区：
文献类型：
--
作者：
Zheng C;Liu M;Ge Y;Qian Y;Fan H
B型肝炎病毒（HBV）感染是肝细胞癌（HCC）的主要病因。HBV X蛋白（HBx）是HBV感染后整合频率最高的病毒基因序列，在肝癌的发病机制中起着重要作用。H3 K27 ac是用于鉴定活性增强子的特征性标记，甚至指示与超级增强子（SE）相关的染色质可及性。在这项研究中，H3 K27 ac ChIP-seq用于HBx诱导的SE的高质量SE注释和染色质可及性评价。结果表明，HBx优先影响H3 K27 ac在转录因子信号通路基因（包括ETV 4）中的富集。RNA-seq表明ETV 4被HBx上调，并且上调的ETV 4促进HCC进展。有趣的是，ETV 4也被包括在Integrative OncoGenomics pipeline获得的568个癌症驱动基因库中。然而，ETV 4的生物学功能和机制仍不完全清楚。在体内和体外，我们发现ETV 4表达增加通过上调DVL 2和激活Wnt/β-catenin促进HCC细胞迁移和侵袭。肝癌组织中ETV 4的mRNA和蛋白水平均高于癌旁组织，ETV 4的高表达与肝癌患者的不良预后相关。总之，我们首先确认ETV 4被HBx显著上调，并参与SE相关的染色质可及性。ETV 4表达增加通过上调DVL 2促进HCC细胞侵袭和转移。本研究提供了HBV相关HCC中ETV 4-DVL 2-β-catenin轴的见解，这将有助于治疗侵袭性HCC患者。
Hepatitis B virus (HBV) infection is the predominant causes of hepatocellular carcinoma (HCC). HBV X protein (HBx), as the most frequently integrated viral gene sequence following HBV infection, plays a critical role in the pathogenesis of HCC. H3K27ac is a characteristic marker for identifying active enhancers and even indicates chromatin accessibility associated with super-enhancers (SEs). In this study, H3K27ac ChIP-seq was applied for high-quality SE annotation of HBx-induced SEs and chromatin accessibility evaluation. The results indicated that HBx preferentially affects enrichment of H3K27ac in transcription factor signaling pathway genes, including ETV4. RNA-seq indicated that ETV4 is upregulated by HBx and that upregulated ETV4 promotes HCC progression. Interestingly, ETV4 was also included in the 568 cancer driver gene pool obtained by the Integrative OncoGenomics pipeline. However, the biological function and mechanism of ETV4 remain incompletely understood. In vivo and in vitro, we found that increased ETV4 expression promotes HCC cell migration and invasion by upregulating DVL2 and activating Wnt/β-catenin. The mRNA and protein levels of ETV4 are higher in tumor tissues compared with adjacent tissues, and high expression of ETV4 is associated with poor prognosis in HCC patients. In summary, we first confirm that ETV4 is significantly upregulated by HBx and involved in SE-associated chromatin accessibility. Increased expression of ETV4 promotes HCC cell invasion and metastasis by upregulating DVL2. The present study provides insight into the ETV4-DVL2-β-catenin axis in HBV-related HCC, which will be helpful for treating patients with aggressive HCC.
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