Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2
Author
Wang, JiaCheng, Peng
Pavlyukov, Marat S.
Yu, Hai
Zhang, Zhuo
Kim, Sung-Hak
Minata, Mutsuko
Mohyeldin, Ahmed
Xie, Wanfu
Chen, Dongquan
Goidts, Violaine
Frett, Brendan
Hu, Wenhao
Li, Hongyu

Shin, Yong Jae
Lee, Yeri
Nam, Do-Hyun
Kornblum, Harley I.
Wang, Maode
Nakano, Ichiro
Affiliation
Univ Arizona, Dept Pharmacol & ToxicolIssue Date
2017-07-24
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AMER SOC CLINICAL INVESTIGATION INCCitation
Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2 2017, 127 (8):3075 Journal of Clinical InvestigationRights
Copyright © 2017, American Society for Clinical Investigation.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Accumulating evidence suggests that glioma stem cells (GSCs) are important therapeutic targets in glioblastoma (GBM). In this study, we identified NIMA-related kinase 2 (NEK2) as a functional binding protein of enhancer of zeste homolog 2 (EZH2) that plays a critical role in the posttranslational regulation of EZH2 protein in GSCs. NEK2 was among the most differentially expressed kinase-encoding genes in GSC-containing cultures (glioma spheres), and it was required for in vitro clonogenicity, in vivo tumor propagation, and radioresistance. Mechanistically, the formation of a protein complex comprising NEK2 and EZH2 in glioma spheres phosphorylated and then protected EZH2 from ubiquitination-dependent protein degradation in a NEK2 kinase activity-dependent manner. Clinically, NEK2 expression in patients with glioma was closely associated with EZH2 expression and correlated with a poor prognosis. NEK2 expression was also substantially elevated in recurrent tumors after therapeutic failure compared with primary untreated tumors in matched GBM patients. We designed a NEK2 kinase inhibitor, compound 3a (CMP3a), which efficiently attenuated GBM growth in a mouse model and exhibited a synergistic effect with radiotherapy. These data demonstrate a key role for NEK2 in maintaining GSCs in GBM by stabilizing the EZH2 protein and introduce the small-molecule inhibitor CMP3a as a potential therapeutic agent for GBM.Note
Authors retain rights to present the work without prior permission in original, revised, adapted, or derivative form, provided that all such use is for personal or nonprofit (and noncommercial) benefit, is consistent with any employment agreement, and references the original publication citation. Examples: reproduction in nonprofit publications; lecture display (slides, overheads, or digitized media); hosting on personal or curriculum vitae-oriented websites; and inclusion in institutional and/or funding-body repositories.ISSN
0021-97381558-8238
PubMed ID
28737508DOI
10.1172/JCI89092Version
Final published versionSponsors
NIH [P01CA163205, R01NS083767, R21CA175875, R01NS087913, R01CA183991, 3T32GM008804-10S1, 5T32GM008804-10]; First Affiliated Hospital of Xi'an Jiaotong University; China Scholar Council; Russian Foundation for Basic Research [16-04-01209]; Russian Federation; Korea Health Technology R&D Project through Korea Health Industry Development Institute (KHIDI); Ministry of Health & Welfare, Republic of Korea [HI14C3418]Additional Links
https://www.jci.org/articles/view/89092ae974a485f413a2113503eed53cd6c53
10.1172/JCI89092
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