zeste 同源物2增强子（EZH2）通过对肾细胞癌中E-钙黏蛋白的表观遗传抑制促进肿瘤细胞迁移和侵袭。

Enhancer of zeste homolog 2 (EZH2) promotes tumour cell migration and invasion via epigenetic repression of E-cadherin in renal cell carcinoma.

作者信息

Liu Li, Xu Zhibing, Zhong Lei, Wang Hang, Jiang Shuai, Long Qilai, Xu Jiejie, Guo Jianming

机构信息

Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.

出版信息

BJU Int. 2016 Feb;117(2):351-62. doi: 10.1111/bju.12702. Epub 2015 Apr 21.

DOI:10.1111/bju.12702

PMID:24612432

Abstract

OBJECTIVE

To investigate the molecular mechanism and clinical significance for an oncogenic role of enhancer of zeste homolog 2 (EZH2) in renal cell carcinoma (RCC).

MATERIALS AND METHODS

Immunohistochemistry analyses of EZH2, histone H3 trimethyl Lys27 (H3K27me3) and E-cadherin were performed in tumour tissue samples from 257 patients with RCC. Regulatory effects of EZH2 on E-cadherin expression were examined by quantitative real-time polymerase chain reaction, Western blot, chromatin immunoprecipitation assay and immunohistochemical staining. Migration and invasion assays were performed in RCC cell lines. Tumour xenograft experiments with RCC cells were carried out in nude mice.

RESULTS

EZH2 promoted migration and invasion in RCC cell lines. Silencing EZH2 with short-hairpin EZH2 (shEZH2) or 3-deazaneplanocin A (DZNep) inhibited migration and invasion (P < 0.001), up-regulated the expression of E-cadherin in vitro, inhibited tumour growth, and prolonged survival in vivo (P = 0.022). EZH2 expression accompanied with E-cadherin repression was associated with advanced disease stage (P = 0.004) and poor overall (P < 0.001) and disease-free survival (P < 0.001).

CONCLUSION

EZH2 may contribute to RCC progression and is a potential therapeutic target for advanced RCC.

摘要

目的

探讨zeste同源物2增强子（EZH2）在肾细胞癌（RCC）中致癌作用的分子机制及临床意义。

材料与方法

对257例RCC患者的肿瘤组织样本进行EZH2、组蛋白H3三甲基赖氨酸27（H3K27me3）和E-钙黏蛋白的免疫组织化学分析。通过定量实时聚合酶链反应、蛋白质免疫印迹法、染色质免疫沉淀试验和免疫组织化学染色检测EZH2对E-钙黏蛋白表达的调控作用。在RCC细胞系中进行迁移和侵袭试验。在裸鼠中进行RCC细胞的肿瘤异种移植实验。

结果

EZH2促进RCC细胞系的迁移和侵袭。用短发夹EZH2（shEZH2）或3-去氮杂氮胞苷（DZNep）沉默EZH2可抑制迁移和侵袭（P < 0.001），在体外上调E-钙黏蛋白的表达，抑制肿瘤生长，并延长体内生存期（P = 0.022）。EZH2表达伴E-钙黏蛋白抑制与疾病晚期（P = 0.004）、总体预后差（P < 0.001）和无病生存期短（P < 0.001）相关。