CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells

Nat Cell Biol. 2011 Jan;13(1):87-94. doi: 10.1038/ncb2139. Epub 2010 Dec 5.

Abstract

Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 (PRC2) and catalyses the trimethylation of histone H3 on Lys 27 (H3K27), which represses gene transcription. EZH2 enhances cancer-cell invasiveness and regulates stem cell differentiation. Here, we demonstrate that EZH2 can be phosphorylated at Thr 487 through activation of cyclin-dependent kinase 1 (CDK1). The phosphorylation of EZH2 at Thr 487 disrupted EZH2 binding with the other PRC2 components SUZ12 and EED, and thereby inhibited EZH2 methyltransferase activity, resulting in inhibition of cancer-cell invasion. In human mesenchymal stem cells, activation of CDK1 promoted mesenchymal stem cell differentiation into osteoblasts through phosphorylation of EZH2 at Thr 487. These findings define a signalling link between CDK1 and EZH2 that may have an important role in diverse biological processes, including cancer-cell invasion and osteogenic differentiation of mesenchymal stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Aminopurine / analogs & derivatives
  • 2-Aminopurine / pharmacology
  • CDC2 Protein Kinase / antagonists & inhibitors
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Differentiation*
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enhancer of Zeste Homolog 2 Protein
  • HEK293 Cells
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / metabolism*
  • Humans
  • Immunoblotting
  • Lysine / metabolism
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Methylation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Phosphorylation
  • Polycomb Repressive Complex 2
  • Protein Binding
  • RNA Interference
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Threonine / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • EED protein, human
  • Histones
  • N(2)-(2-aminocyclohexyl)-N(6)-(3-chlorophenyl)-9-ethyl-9H-purine-2,6-diamine
  • Nuclear Proteins
  • Repressor Proteins
  • SUZ12 protein, human
  • Transcription Factors
  • Threonine
  • 2-Aminopurine
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Histone-Lysine N-Methyltransferase
  • Polycomb Repressive Complex 2
  • CDC2 Protein Kinase
  • Lysine