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Retraction Free access | 10.1172/JCI144618

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, Hongyu Li, Yong Jae Shin, Yeri Lee, Do-Hyun Nam, Harley I. Kornblum, Maode Wang, and Ichiro Nakano

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Published October 12, 2020 - More info

Published in Volume 130, Issue 11 on November 2, 2020
J Clin Invest. 2020;130(11):6187–6187. https://doi.org/10.1172/JCI144618.
© 2020 American Society for Clinical Investigation
Published October 12, 2020 - Version history
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Related article:

Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2
Jia Wang, … , Maode Wang, Ichiro Nakano
Jia Wang, … , Maode Wang, Ichiro Nakano
Research Article Oncology Stem cells

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

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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.

Authors

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, Hongyu Li, Yong Jae Shin, Yeri Lee, Do-Hyun Nam, Harley I. Kornblum, Maode Wang, Ichiro Nakano

×

Original citation: J Clin Invest. 2017;127(8):3075–3089. https://doi.org/10.1172/JCI89092

Citation for this retraction: J Clin Invest. 2020;130(11):6187. https://doi.org/10.1172/JCI144618

At the request of the corresponding author, the JCI is retracting this article. Several concerns were raised regarding the Western blot data in Figures 1J, 2A, 3A, and 4D and Supplemental Figures 3A, 4C, and 6A. After an extensive internal review, it became apparent that errors were introduced during the preparation of the revised figures. Due to loss of confidence in the published figures, the corresponding author requested retraction. No issues have been raised with regard to any of the other data in the paper.

Footnotes

See the related article at Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2.

Version history
  • Version 1 (October 12, 2020): Electronic publication
  • Version 2 (November 2, 2020): Print issue publication

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