Wei, Y, Chen, YH, Li, LY, Lang, J, Yeh, SP, Shi, B et al.. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat Cell Biol 13: 87-94

Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Nature Cell Biology (Impact Factor: 19.68). 01/2011; 13(1):87-94. DOI: 10.1038/ncb2139
Source: PubMed


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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    • "Moreover, NIPP1 maintains EZH2 phosphorylation by inhibiting its dephosphorylation by PP1 [78]. It has been showed that CDK1 phosphorylates EZH2 at T487 and that the phosphorylation induces the dissociation of EZH2 from PRC2, resulting in the inactivation of EZH2 and a reduction in cancer cell invasion [77]. In contrast, EZH2 phosphorylation at T345 promotes cell migration and proliferation [75]. "
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    ABSTRACT: Polycomb repressive complex 2 (PRC2) is the epigenetic regulator that induces histone H3 lysine 27 methylation (H3K27me3) and silences specific gene transcription. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of PRC2, and evidence shows that EZH2 plays an essential role in cancer initiation, development, progression, metastasis, and drug resistance. EZH2 expression is indeed regulated by various oncogenic transcription factors, tumor suppressor miRNAs, and cancer-associated non-coding RNA. EZH2 activity is also controlled by post-translational modifications, which are deregulated in cancer. The canonical role of EZH2 is gene silencing through H3K27me3, but accumulating evidence shows that EZH2 methlyates substrates other than histone and has methylase-independent functions. These non-canonical functions of EZH2 are shown to play a role in cancer progression. In this review, we summarize current information on the regulation and roles of EZH2 in cancer. We also discuss various therapeutic approaches to targeting EZH2.
    Full-text · Article · Jul 2014 · Cancer Research and Treatment
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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.
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    • "All transfections were performed using Effectene reagent (QIAGEN) according to the manufacturer's instructions. Cell synchronization was performed as previously mentioned elsewhere (15,27,28). "
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    ABSTRACT: Although several studies have suggested that the functions of heterochromatin regulators may be regulated by post-translational modifications during cell cycle progression, regulation of the histone methyltransferase Suv39H1 is not fully understood. Here, we demonstrate a direct link between Suv39H1 phosphorylation and cell cycle progression. We show that CDK2 phosphorylates Suv39H1 at Ser391 and these phosphorylation levels oscillate during the cell cycle, peaking at S phase and maintained during S-G2-M phase. The CDK2-mediated phosphorylation of Suv39H1 at Ser391 results in preferential dissociation from chromatin. Furthermore, phosphorylation-mediated dissociation of Suv39H1 from chromatin causes an enhanced occupancy of JMJD2A histone demethylase on heterochromatin and alterations in inactive histone marks. Overexpression of phospho-mimic Suv39H1 induces early replication of heterochromatin, suggesting the importance of Suv39H1 phosphorylation in the replication of heterochromatin. Moreover, overexpression of phospho-defective Suv39H1 caused altered replication timing of heterochromatin and increases sensitivity to replication stress. Collectively, our data suggest that phosphorylation-mediated modulation of Suv39H1-chromatin association may be an initial step in heterochromatin replication.
    Full-text · Article · Apr 2014 · Nucleic Acids Research
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