Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells
Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells
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DOI：
10.1111/j.1349-7006.2008.00743.x
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发表时间：
2008-04-01
期刊：
影响因子：
5.7
通讯作者：
Ochiai, Atsushi
中科院分区：
文献类型：
--
作者：
Fujii, Satoshi;Ochiai, Atsushi
zeste增强子同源物2（EZH 2）（一种表观遗传阻遏物）的过表达发生在各种恶性肿瘤中，并且与不良预后相关;然而，EZH 2过表达在癌症与非癌组织中的功能作用仍不清楚。在这项研究中，我们发现EZH 2和E-cadherin基因在胃癌细胞中的表达呈负相关。在胃癌细胞中通过短干扰RNA敲低EZH 2导致E-cadherin基因的恢复。我们发现EZH 2复合物与组蛋白H3和Lys 27存在，它们在胃癌细胞中的E-cadherin启动子区域甲基化。E-cadherin基因的恢复与E-cadherin基因启动子区DNA甲基化状态的改变无关。免疫荧光染色证实，在敲低EZH 2后，细胞膜中存在的E-cadherin蛋白的表达恢复，导致癌症表型的改变，例如其侵袭能力。在体内，EZH 2蛋白和E-cadherin蛋白在胃癌组织中的表达在个体细胞水平上呈负相关。本研究提供了EZH 2在胃癌细胞中过表达的功能作用的潜在机制，以及在肿瘤抑制基因沉默机制中调节E-cadherin表达的新模式。我们目前的研究为探索阻断EZH 2过表达作为治疗癌症的新方法铺平了道路。
Overexpression of enhancer of zeste homolog 2 (EZH2), an epigenetic repressor, occurs in various malignancies and is associated with poor prognosis; however, the functional role of EZH2 overexpression in cancer versus non-cancerous tissue remains unclear. In this study, we found an inverse correlation between EZH2 and E-cadherin gene expression in gastric cancer cells. Knockdown of EZH2 by short interfering RNA in gastric cancer cells resulted in a restoration of the E-cadherin gene. We showed that the EZH2 complex existed with histone H3 and Lys27, which were methylated on E-cadherin promoter regions in gastric cancer cells. The restoration of E-cadherin was not involved in the change of the DNA methylation status in the E-cadherin promoter region. Immunofluorescence staining confirmed the expression of E-cadherin protein present in the cell membrane was restored after knockdown of EZH2, resulting in changing the cancer phenotype, such as its invasive capacity. In vivo, the relationship of inverse expression between EZH2 protein and E-cadherin protein was observed at the individual cellular level in gastric cancer tissue. This study provides into the mechanisms underlying the functional role of EZH2 overexpression in gastric cancer cells and a new modality of regulation of E-cadherin expression in silencing mechanisms of tumor suppressor genes. Our present study paves the way for exploring the blockade of EZH2 overexpression as a novel approach to treating cancer.