Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2

Persistent Link:
http://hdl.handle.net/10150/625489
Title:
Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2
Author:
Wang, Jia; Cheng, 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 & Toxicol
Issue Date:
2017-07-24
Publisher:
AMER SOC CLINICAL INVESTIGATION INC
Citation:
Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2 2017, 127 (8):3075 Journal of Clinical Investigation
Journal:
Journal of Clinical Investigation
Rights:
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:
0021-9738; 1558-8238
PubMed ID:
28737508
DOI:
10.1172/JCI89092
Version:
Final published version
Sponsors:
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/89092

Full metadata record

DC FieldValue Language
dc.contributor.authorWang, Jiaen
dc.contributor.authorCheng, Pengen
dc.contributor.authorPavlyukov, Marat S.en
dc.contributor.authorYu, Haien
dc.contributor.authorZhang, Zhuoen
dc.contributor.authorKim, Sung-Haken
dc.contributor.authorMinata, Mutsukoen
dc.contributor.authorMohyeldin, Ahmeden
dc.contributor.authorXie, Wanfuen
dc.contributor.authorChen, Dongquanen
dc.contributor.authorGoidts, Violaineen
dc.contributor.authorFrett, Brendanen
dc.contributor.authorHu, Wenhaoen
dc.contributor.authorLi, Hongyuen
dc.contributor.authorShin, Yong Jaeen
dc.contributor.authorLee, Yerien
dc.contributor.authorNam, Do-Hyunen
dc.contributor.authorKornblum, Harley I.en
dc.contributor.authorWang, Maodeen
dc.contributor.authorNakano, Ichiroen
dc.date.accessioned2017-09-13T23:39:49Z-
dc.date.available2017-09-13T23:39:49Z-
dc.date.issued2017-07-24-
dc.identifier.citationTargeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2 2017, 127 (8):3075 Journal of Clinical Investigationen
dc.identifier.issn0021-9738-
dc.identifier.issn1558-8238-
dc.identifier.pmid28737508-
dc.identifier.doi10.1172/JCI89092-
dc.identifier.urihttp://hdl.handle.net/10150/625489-
dc.description.abstractAccumulating 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.en
dc.description.sponsorshipNIH [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]en
dc.language.isoenen
dc.publisherAMER SOC CLINICAL INVESTIGATION INCen
dc.relation.urlhttps://www.jci.org/articles/view/89092en
dc.rightsCopyright © 2017, American Society for Clinical Investigationen
dc.titleTargeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2en
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Dept Pharmacol & Toxicolen
dc.identifier.journalJournal of Clinical Investigationen
dc.description.noteAuthors 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.en
dc.description.collectioninformationThis 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.en
dc.eprint.versionFinal published versionen

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