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.
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Bachmann, I. M.et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J. Clin. Oncol.24, 268–273 (2006).
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Jer-Yen Yang &
Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan.
Chun-Yi Lin &
Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
Long-Yuan Li &
Asia University, Taichung 413, Taiwan.
Long-Yuan Li &
Division of Hematology and Oncology, Department of Medicine, China Medical University and Hospital, Taichung 404, Taiwan.
Graduate Institute of Chinese Medical Science, China Medical University, Taichung 404, Taiwan.
Institute of Molecular Biology, National Chung Hsing University, Taichung 402, Taiwan.
Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
M.-C.H., Y.W. and L.-Y.L. designed the project and wrote the paper. M.-C.H. and L.-Y.L. supervised the research. Y.W. performed most of the experiments in Figs 1, 2, 3. Y.-H.C. performed mesenchymal stem cell experiments in Figs 4 and 5 and experiments investigating the interaction between EZH2 and CDK1. C.-C.L. performed the mass spectrometry analysis. C.-Y.L. generated and characterized the phospho-EZH2 antibody. S.-P.Y. collected and characterized primary human mesenchymal stem cells. J. L., B.S., C. -C.Y. and J.-Y.Y. assisted with experiments. All authors participated in interpreting the results.
Competing financial interests
The authors declare no competing financial interests.