Qi Ying, Zhang Xiaoli, Kang Yani, Wu Jun, Chen Jian, Li Hua, Guo Yan, Liu Bingya, Shao Zhifeng, Zhao Xiaodong
Shanghai Center for Systems Biomedicine, State Key laboratory on Oncogenes and Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Rd., Shanghai 200240, China.
Mol Biosyst. 2015 Jul;11(7):1980-6. doi: 10.1039/c5mb00233h.
A histone methyltransferase enhancer of zeste homologue 2 (EZH2) catalyzes trimethylation at histone H3 lysine27 (H3K27me3) and is frequently dysregulated in a wide range of human cancers. EZH2-mediated gene silencing contributes to carcinogenesis and regulates stem cell maintenance and differentiation; however, the underlining mechanisms remain to be completely understood. Here, we found that downregulation of EZH2 by RNA interference (RNAi) in gastric cancer cells suppresses cell growth, migration, invasion, and induces cell cycle arrest. Transcriptome analysis identified 1223 EZH2 responsive genes upon EZH2 knockdown. These genes are involved in the biological processes of cell cycle, proliferation and metastasis. Particularly, we found that annexin A6 (ANXA6) is a new target of EZH2 and is repressed in gastric cancer cells. Restoration of ANXA6 expression inhibits gastric cellular proliferation. We further demonstrated that EZH2-mediated H3K27me3, rather than promoter DNA methylation, is primarily responsible for ANXA6 inhibition. Taken together, our results provide a framework for understanding EZH2 biology and reveal ANXA6 as a new EZH2 target involving gastric cellular proliferation.
组蛋白甲基转移酶zeste同源物2（EZH2）催化组蛋白H3赖氨酸27（H3K27me3）的三甲基化，在多种人类癌症中经常发生失调。EZH2介导的基因沉默有助于致癌作用，并调节干细胞的维持和分化；然而，其潜在机制仍有待完全了解。在此，我们发现通过RNA干扰（RNAi）下调胃癌细胞中的EZH2可抑制细胞生长、迁移、侵袭，并诱导细胞周期停滞。转录组分析确定了EZH2敲低后1223个EZH2反应基因。这些基因参与细胞周期、增殖和转移的生物学过程。特别地，我们发现膜联蛋白A6（ANXA6）是EZH2的一个新靶点，在胃癌细胞中受到抑制。ANXA6表达的恢复抑制胃细胞增殖。我们进一步证明，EZH2介导的H3K27me3而非启动子DNA甲基化是ANXA6抑制的主要原因。综上所述，我们的结果为理解EZH2生物学提供了一个框架，并揭示ANXA6是涉及胃细胞增殖的一个新的EZH2靶点。
