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

Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21360-5. doi: 10.1073/pnas.1210371110. Epub 2012 Dec 10.

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 / drug effects
  • Apoptosis / genetics
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Embryo, Mammalian / cytology
  • Enhancer of Zeste Homolog 2 Protein
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockout Techniques
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / metabolism
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / pathology*
  • Methylation / drug effects
  • Mice
  • Mutation / genetics
  • Phenotype
  • Polycomb Repressive Complex 2 / antagonists & inhibitors*
  • Polycomb Repressive Complex 2 / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Tumor Stem Cell Assay
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Histones
  • Small Molecule Libraries
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Polycomb Repressive Complex 2

Associated data

  • GEO/GSE41315