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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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2-Aminopurine / analogs & derivatives
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2-Aminopurine / pharmacology
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CDC2 Protein Kinase / antagonists & inhibitors
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CDC2 Protein Kinase / genetics
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CDC2 Protein Kinase / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Differentiation*
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Cell Line
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Cell Line, Tumor
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Cell Movement
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enhancer of Zeste Homolog 2 Protein
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HEK293 Cells
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HeLa Cells
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Histone-Lysine N-Methyltransferase / metabolism
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Histones / metabolism*
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Humans
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Immunoblotting
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Lysine / metabolism
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Mesenchymal Stem Cells / cytology
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Mesenchymal Stem Cells / metabolism*
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Methylation
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Neoplasm Proteins
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Osteoblasts / cytology
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Osteoblasts / metabolism
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Phosphorylation
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Polycomb Repressive Complex 2
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Protein Binding
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RNA Interference
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Threonine / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Carrier Proteins
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DNA-Binding Proteins
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EED protein, human
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Histones
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N(2)-(2-aminocyclohexyl)-N(6)-(3-chlorophenyl)-9-ethyl-9H-purine-2,6-diamine
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Neoplasm Proteins
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Nuclear Proteins
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Repressor Proteins
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SUZ12 protein, human
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Transcription Factors
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Threonine
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2-Aminopurine
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Histone-Lysine N-Methyltransferase
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Polycomb Repressive Complex 2
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CDC2 Protein Kinase
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Lysine