Hepatitis C virus core upregulates the methylation status of the RASSF1A promoter through regulation of SMYD3 in hilar cholangiocarcinoma cells
Hepatitis C virus core upregulates the methylation status of the RASSF1A promoter through regulation of SMYD3 in hilar cholangiocarcinoma cells
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丙型肝炎病毒核心通过调节肝门部胆管癌细胞中的SMYD3上调RASSF1A启动子的甲基化状态
DOI：
10.1093/abbs/gmr021
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发表时间：
2011-05-01
影响因子：
3.7
通讯作者：
Lin, Qing
中科院分区：
文献类型：
--
作者：
Guo, Ning;Chen, Rufu;Lin, Qing
越来越多的证据表明表观遗传调控在肿瘤发生中的重要作用。之前，我们观察到丙型肝炎病毒核心（HCVc）蛋白转染导致正常胆管细胞恶性转化，并且肿瘤抑制基因RASSF1A在许多肝门胆管癌患者中通过启动子区域的高甲基化而下调。在本研究中，我们发现SET和MYND结构域蛋白3 (SMYD3)，一种新型组蛋白甲基转移酶，在胆管癌患者中过度表达，特别是在HCV感染患者中。HCVc转染肝门胆管癌细胞系QBC939和FRH0201后，可上调SMYD3的表达，促进细胞生长，这与我们的临床研究结果一致。这一现象提示SMYD3与HCV感染后胆管癌发生的表观遗传调控有关。过表达SMYD3可以抑制RASSF1A的表达，而siRNA抑制SMYD3则可以提高RASSF1A的表达。甲基化特异性聚合酶链反应（MS-PCR）结果显示，RASSF1A启动子的甲基化状态受SMYD3调控。综上所述，HCVc可通过调控SMYD3上调RASSF1A启动子的甲基化状态，组蛋白甲基化可能以未知的机制影响下游基因的DNA甲基化。
Increasing evidence has been accumulated indicating the important role of epigenetic regulation in tumor genesis. Previously, we observed that the transfection of hepatitis C virus core (HCVc) protein led to malignant transformation in normal biliary cells, and that tumor suppressor gene RASSF1A was downregulated in many hilar cholangiocarcinoma patients by hypermethylation in the promoter region. In the present study, we found SET and MYND domain-containing protein 3 (SMYD3), a novel histone methyltransferase, was overexpressed in cholangiocarcinoma patients especially in those with HCV infection. Transfection of HCVc into hilar cholangiocarcinoma cell lines QBC939 and FRH0201 could upregulate the expression of SMYD3 and promote cell growth, which was consistent with the results of our clinical research. This phenomenon indicated that SMYD3 was related to the epigenetic regulation of cholangiocarcinoma genesis with HCV infection. Overexpression of SMYD3 could inhibit RASSF1A expression, whereas inhibition of SMYD3 by siRNA improved its expression. Methylation-specific polymerase chain reaction (MS-PCR) results showed the methylation status of RASSF1A promoter was regulated by SMYD3. In conclusion, HCVc could upregulate the methylation status of the RASSF1A promoter through regulation of SMYD3, and histone methylation may affect the DNA methylation of downstream gene by an unknown mechanism.