The State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
Oncogene. 2012 Feb 2;31(5):583-94. doi: 10.1038/onc.2011.254. Epub 2011 Jun 20.
The enhancer of zeste homolog 2 (EZH2) is upregulated and has an oncogenic role in several types of human cancer. However, the abnormalities of EZH2 and its underlying mechanisms in the pathogenesis of nasopharyngeal carcinoma (NPC) remain unknown. In this study, we found that high expression of EZH2 in NPC was associated closely with an aggressive and/or poor prognostic phenotype (P<0.05). In NPC cell lines, knockdown of EZH2 by short hairpin RNA was sufficient to inhibit cell invasiveness/metastasis both in vitro and in vivo, whereas ectopic overexpression of EZH2 supported NPC cell invasive capacity with a decreased expression of E-cadherin. In addition, ablation of endogenous Snail in NPC cells virtually totally prevented the repressive activity of EZH2 to E-cadherin, indicating that Snail might be a predominant mediator of EZH2 to suppress E-cadherin. Furthermore, co-immunoprecipitation (IP), chromatin IP and luciferase reporter assays demonstrated that in NPC cells, (1) EZH2 interacted with HDAC1/HDAC2 and Snail to form a repressive complex; (2) these components interact in a linear fashion, not in a triangular fashion, that is, HDAC1 or HDAC2 bridge the interaction between EZH2 and Snail; and (3) the EZH2/HDAC1/2/Snail complex could closely bind to the E-cadherin promoter by Snail, but not YY1, to repress E-cadherin. The data provided in this report suggest a critical role of EZH2 in the control of cell invasion and/or metastasis by forming a co-repressor complex with HDAC1/HDAC2/Snail to repress E-cadherin, an activity that might be responsible, at least in part, for the development and/or progression of human NPCs.
增强子结合锌指蛋白 2（EZH2）在几种类型的人类癌症中上调并具有致癌作用。然而，EZH2 的异常及其在鼻咽癌（NPC）发病机制中的潜在机制尚不清楚。在本研究中，我们发现 NPC 中 EZH2 的高表达与侵袭性和/或不良预后表型密切相关（P<0.05）。在 NPC 细胞系中，短发夹 RNA 敲低 EZH2 足以抑制体外和体内的细胞侵袭/转移，而 EZH2 的异位过表达支持 NPC 细胞的侵袭能力，同时降低 E-钙粘蛋白的表达。此外，NPC 细胞中内源性 Snail 的缺失几乎完全阻止了 EZH2 对 E-钙粘蛋白的抑制活性，表明 Snail 可能是 EZH2 抑制 E-钙粘蛋白的主要介质。此外，共免疫沉淀（IP）、染色质 IP 和荧光素酶报告基因测定表明，在 NPC 细胞中，（1）EZH2 与 HDAC1/HDAC2 和 Snail 相互作用形成抑制复合物；（2）这些成分以线性方式而不是三角形方式相互作用，即 HDAC1 或 HDAC2 桥接 EZH2 和 Snail 之间的相互作用；（3）EZH2/HDAC1/2/Snail 复合物可以通过 Snail 紧密结合到 E-钙粘蛋白启动子上，而不是 YY1，从而抑制 E-钙粘蛋白。本报告提供的数据表明，EZH2 通过与 HDAC1/HDAC2/Snail 形成共抑制复合物来抑制 E-钙粘蛋白，从而在控制细胞侵袭和/或转移中发挥关键作用，这种活性可能至少部分负责人类 NPC 的发生和/或进展。
