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

Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Nature Cell Biology (Impact Factor: 20.06). 01/2011; 13(1):87-94. DOI: 10.1038/ncb2139
Source: PubMed

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.

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    • "Among the pivotal regulators, enhancer of zeste homologue 2 (EZH2), a Polycomb Group (PcG) protein homologous to Drosophila enhancer of zeste, is involved in gene silencing (Kleer et al, 2003). EZH2 catalyses the addition of methyl groups to histone H3 at Lys 27 (H3K27) forming H3K27me3, the activated form of H3K27, in target gene promoters, leading to epigenetic silencing (Wei et al, 2011). EZH2 is reported to be over-expressed, amplified and with an altered localisation in lymphoma or acute myeloid leukaemia (AML) (Roman-Gomez et al, 2007; Strathdee et al, 2007). "
    R Qin · K Li · X Qi · X Zhou · L Wang · P Zhang · L Zou
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    ABSTRACT: Background:β-Arrestins are scaffold proteins that interact with various cellular signals. Although β-arrestin2 mediates the initiation and progression of myeloid leukaemia, the critical role of β-arrestin1 in the chronic myeloid leukaemia (CML) is still unknown. The aim of this study is to investigate the essential function of β-arrestin1 in CML.Methods:The expressions of β-arrestin1 and BCR/ABL in CML patients, animal models and K562 cells were measured by RT-PCR, immunofluorescence and western blotting. The effect of β-arrestin1 on CML animal models and K562 cells by colony formation, MTT and survival analysis were assessed. BCR/ABL H4 acetylation was analysed through the use of Chromatin-immunoprecipitation (ChIP) -on-chip and confirmed by ChIP respectively. Co-immunoprecipitation and confocal were examined for the binding of β-arrestin1 with enhancer of zeste homologue 2 (EZH2).Results:The higher expression of β-arrestin1 is positively correlated with clinical phases of CML patients. Depletion of β-arrestin1 decelerates progression of K562 and primary cells, and increases survival of CML mice. Importantly, silenced β-arrestin1 results in the decrease of BCR/ABL H4 acetylation level in K562 cells. Further data illustrate that nuclear β-arrestin1 binds to EZH2 to mediate BCR/ABL acetylation and thus regulates cell progression in K562 cells and the survival of CML mice.Conclusions:Our findings reveal a novel function of β-arrestin1 binding to EZH2 to promote CML progression by regulating BCR/ABL H4 acetylation.British Journal of Cancer advance online publication, 17 June 2014; doi:10.1038/bjc.2014.335
    British Journal of Cancer 06/2014; 111(3). DOI:10.1038/bjc.2014.335 · 4.82 Impact Factor
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    • "Myoblast proliferation through inhibition of MyoD Yes NSC self-renewal through inhibition of Ngn2 Yes Ali et al., 2011 Epigenetic regulation through Ezh2 and Dnmt1 Yes Chen et al., 2010; Kaneko et al., 2010; Wei et al., 2011; Wu and Zhang, 2011; Lavoie and St-Pierre, 2011 "
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    ABSTRACT: Cyclin-dependent kinases (Cdks) are serine/threonine kinases and their catalytic activities are modulated by interactions with cyclins and Cdk inhibitors (CKIs). Close cooperation between this trio is necessary for ensuring orderly progression through the cell cycle. In addition to their well-established function in cell cycle control, it is becoming increasingly apparent that mammalian Cdks, cyclins and CKIs play indispensable roles in processes such as transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions and spermatogenesis. Even more remarkably, they can accomplish some of these tasks individually, without the need for Cdk/cyclin complex formation or kinase activity. In this Review, we discuss the latest revelations about Cdks, cyclins and CKIs with the goal of showcasing their functional diversity beyond cell cycle regulation and their impact on development and disease in mammals.
    Development 08/2013; 140(15):3079-93. DOI:10.1242/dev.091744 · 6.27 Impact Factor
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    • "The protein kinase AKT phosphorylates EZH2 at serine 21, which inhibits PRC2-mediated H3K27me3 and gene silencing but activates Polycomb-independent oncogenic functions of EZH2 (Cha et al, 2005; Xu et al, 2012). Cyclindependent kinase 1 (CDK1) and CDK2 phosphorylate EZH2 at threonine 350 (T350) and 487 (T487) residues and regulate PRC2 recruitment to its target loci (Chen et al, 2010; Kaneko et al, 2010; Wei et al, 2011). T350 phosphorylation also enhances EZH2 binding to HOTAIR and XIST ncRNAs and accelerates turnover of phosphorylated EZH2 (Kaneko et al, 2010; Wu and Zhang, 2011). "
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    ABSTRACT: The Polycomb-repressive complex 2 (PRC2) is important for maintenance of stem cell pluripotency and suppression of cell differentiation by promoting histone H3 lysine 27 trimethylation (H3K27me3) and transcriptional repression of differentiation genes. Here we show that the tumour-suppressor protein BRCA1 interacts with the Polycomb protein EZH2 in mouse embryonic stem (ES) and human breast cancer cells. The BRCA1-binding region in EZH2 overlaps with the noncoding RNA (ncRNA)-binding domain, and BRCA1 expression inhibits the binding of EZH2 to the HOTAIR ncRNA. Decreased expression of BRCA1 causes genome-wide EZH2 re-targeting and elevates H3K27me3 levels at PRC2 target loci in both mouse ES and human breast cancer cells. BRCA1 deficiency blocks ES cell differentiation and enhances breast cancer migration and invasion in an EZH2-dependent manner. These results reveal that BRCA1 is a key negative modulator of PRC2 and that loss of BRCA1 inhibits ES cell differentiation and enhances an aggressive breast cancer phenotype by affecting PRC2 function.
    The EMBO Journal 04/2013; 32(11). DOI:10.1038/emboj.2013.95 · 10.75 Impact Factor
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