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    MELK mediates the stability of EZH2 through site-specific phosphorylation in extranodal natural killer/ T-cell lymphoma

    Access Status
    Fulltext not available
    Authors
    Li, B.
    Yan, J.
    Phyu, T.
    Fan, S.
    Chung, T.H.
    Mustafa, N.
    Lin, B.
    Wang, L.
    Eichhorn, Pieter
    Goh, B.C.
    Ng, S.B.
    Kappei, D.
    Chng, W.J.
    Date
    2019
    Type
    Journal Article
    
    Metadata
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    Citation
    Li, B. and Yan, J. and Phyu, T. and Fan, S. and Chung, T.H. and Mustafa, N. and Lin, B. et al. 2019. MELK mediates the stability of EZH2 through site-specific phosphorylation in extranodal natural killer/ T-cell lymphoma. Blood. 134 (23): pp. 2046-2058.
    Source Title
    Blood
    DOI
    10.1182/blood.2019000381
    ISSN
    0006-4971
    Faculty
    Faculty of Health Sciences
    School
    School of Pharmacy and Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/77889
    Collection
    • Curtin Research Publications
    Abstract

    Oncogenic EZH2 is overexpressed and extensively involved in the pathophysiology of different cancers including extranodal natural killer/T-cell lymphoma (NKTL). However, the mechanisms regarding EZH2 upregulation is poorly understood, and it still remains untargetable in NKTL. In this study, we examine EZH2 protein turnover in NKTL and identify MELK kinase as a regulator of EZH2 ubiquitination and turnover. Using quantitative mass spectrometry analysis, we observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. MELK inhibition through both chemical and genetic means led to ubiquitination and destabilization of EZH2 protein. Importantly, we determine that MELK is upregulated in NKTL, and its expression correlates with EZH2 protein expression as determined by tissue microarray derived from NKTL patients. FOXM1, which connected MELK to EZH2 signaling in glioma, was not involved in mediating EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme that deubiquitinates EZH2 at K222. These findings uncover an important role of MELK and USP36 in mediating EZH2 stability in NKTL. Moreover, MELK overexpression led to decreased sensitivity to bortezomib treatment in NKTL based on deprivation of EZH2 ubiquitination. Therefore, modulation of EZH2 ubiquitination status by targeting MELK may be a new therapeutic strategy for NKTL patients with poor bortezomib response.

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