Journal Article

Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation

Yang, Teddy, Feng, Grace, Li, Min, Yan, Xiaoxia, Zhang, Ruipeng, Qi, Wei, Liu, Xianghui, Lin, Ying, Li, En, Lu, Chris X., Ardayfio, Ophelia, Li, Ling, Fang, Jialuo, Zhou, Tao, Zhao, Kehao, Zhang, Man, Atadja, Peter, Zeng, Jue, Chuai, Shannon, Li, Guobin, Mi, Yuan, Yu, Zhengtian, Chen, Zijun, Fan, Hong, Chan, HoMan, Zhang, Ji-Hu, Tenga, Lin, Gu, Justin

2012

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / apoptosis / Apoptosis - drug effects / Apoptosis - genetics / B cell lymphoma / B lymphocytes / Biological Sciences / Cell cycle / cell cycle checkpoints / Cell Cycle Checkpoints - drug effects / Cell Cycle Checkpoints - genetics / Cell growth / Cell Line, Tumor / Cell lines / cell proliferation / Cell Proliferation - drug effects / Cyclin-Dependent Kinase Inhibitor p16 - metabolism / DNA methylation / Down-Regulation - drug effects / Down-Regulation - genetics / Embryo, Mammalian - cytology / embryogenesis / Embryonic growth stage / English language learners / Enhancer of Zeste Homolog 2 Protein / Enzymatic activity / enzyme activity / Enzymes / Fibroblasts - drug effects / Fibroblasts - metabolism / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - drug effects / Gene Knockout Techniques / genes / Genetic mutation / Histone-Lysine N-Methyltransferase - metabolism / Histones / Histones - metabolism / Lymphoma / Lymphoma, Large B-Cell, Diffuse - genetics / Lymphoma, Large B-Cell, Diffuse - pathology / lysine / methionine / Methylation / Methylation - drug effects / Mice / Mutation / Mutation - genetics / neoplasm cells / Phenotype / Polycomb Repressive Complex 2 - antagonists & inhibitors / Polycomb Repressive Complex 2 - metabolism / Proteins / Small Molecule Libraries - chemistry / Small Molecule Libraries - pharmacology / Stem cells / Tumor Stem Cell Assay / Up-Regulation - drug effects / Up-Regulation - genetics