1. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation.
- Author
-
Wei Qi, Chan, HoMan, Lin Teng, Ling Li, Chuai, Shannon, Ruipeng Zhang, Jue Zeng, Min Li, Hong Fan, Ying Lin, Gu, Justin, Ardayfio, Ophelia, Ji-Hu Zhang, Xiaoxia Yan, Jialuo Fang, Yuan Mi, Man Zhang, Tao Zhou, Feng, Grace, and Zijun Chen
- Subjects
CONTACT inhibition ,CANCER cells ,CELL proliferation ,GENE expression ,GENETIC mutation ,HISTONES - Abstract
Ezh2 (Enhancer of zeste homolog 2) protein is the enzymatic component of the Polycomb repressive complex 2 (PRC2), which represses gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of Ezh2 were identified in diffused large B-cell lymphomas and follicular lymphomas. To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine. EI1-treated cells exhibit genome-wide loss of H3K27 methylation and activation of PRC2 target genes. Furthermore, inhibition of Ezh2 by EI1 in diffused large B-cell lymphomas cells carrying the Y641 mutations results in decreased proliferation, cell cycle arrest, and apoptosis. These results provide strong validation of Ezh2 as a potential therapeutic target for the treatment of cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF