Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation.
Proc Natl Acad Sci U S A, 2012/12/26;109(52):21360-5.
Qi W[1], Chan H, Teng L, Li L, Chuai S, Zhang R, Zeng J, Li M, Fan H, Lin Y, Gu J, Ardayfio O, Zhang JH, Yan X, Fang J, Mi Y, Zhang M, Zhou T, Feng G, Chen Z, Li G, Yang T, Zhao K, Liu X, Yu Z, Lu CX, Atadja P, Li E
Affiliations
PMID: 23236167DOI: 10.1073/pnas.1210371110
Impact factor: 12.779
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.
MeSH terms
Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16; Down-Regulation; Embryo, Mammalian; Enhancer of Zeste Homolog 2 Protein; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Histone-Lysine N-Methyltransferase; Histones; Lymphoma, Large B-Cell, Diffuse; Methylation; Mice; Mutation; Phenotype; Polycomb Repressive Complex 2; Small Molecule Libraries; Tumor Stem Cell Assay; Up-Regulation
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