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

Jia Wang, Peng Cheng, Marat S. Pavlyukov, Hai Yu, Zhuo Zhang, Sung Hak Kim, Mutsuko Minata, Ahmed Mohyeldin, Wanfu Xie, Dongquan Chen, Violaine Goidts, Brendan Frett, Wenhao Hu, Hong Yu Li, Yong Jae Shin, Yeri Lee, Do Hyun Nam, Harley I. Kornblum, Maode Wang, Ichiro Nakano

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3075-3089
Number of pages15
JournalJournal of Clinical Investigation
Volume127
Issue number8
DOIs
StatePublished - Aug 1 2017

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Glioblastoma
Glioma
Growth
Stem Cells
Phosphotransferases
Neoplasms
NIMA-Related Kinases
Enhancer of Zeste Homolog 2 Protein
histone methyltransferase
Ubiquitination
Proteolysis
Carrier Proteins
Radiotherapy
Therapeutics
Cell Culture Techniques
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2. / 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, Hong Yu; Shin, Yong Jae; Lee, Yeri; Nam, Do Hyun; Kornblum, Harley I.; Wang, Maode; Nakano, Ichiro.

In: Journal of Clinical Investigation, Vol. 127, No. 8, 01.08.2017, p. 3075-3089.

Research output: Contribution to journalArticle

Wang, J, Cheng, P, Pavlyukov, MS, Yu, H, Zhang, Z, Kim, SH, Minata, M, Mohyeldin, A, Xie, W, Chen, D, Goidts, V, Frett, B, Hu, W, Li, HY, Shin, YJ, Lee, Y, Nam, DH, Kornblum, HI, Wang, M & Nakano, I 2017, 'Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2', Journal of Clinical Investigation, vol. 127, no. 8, pp. 3075-3089. https://doi.org/10.1172/JCI89092
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, Hong Yu ; Shin, Yong Jae ; Lee, Yeri ; Nam, Do Hyun ; Kornblum, Harley I. ; Wang, Maode ; Nakano, Ichiro. / Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 8. pp. 3075-3089.
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T1 - Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2

AU - Wang, Jia

AU - Cheng, Peng

AU - Pavlyukov, Marat S.

AU - Yu, Hai

AU - Zhang, Zhuo

AU - Kim, Sung Hak

AU - Minata, Mutsuko

AU - Mohyeldin, Ahmed

AU - Xie, Wanfu

AU - Chen, Dongquan

AU - Goidts, Violaine

AU - Frett, Brendan

AU - Hu, Wenhao

AU - Li, Hong Yu

AU - Shin, Yong Jae

AU - Lee, Yeri

AU - Nam, Do Hyun

AU - Kornblum, Harley I.

AU - Wang, Maode

AU - Nakano, Ichiro

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N2 - 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.

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