Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2
Authors: Do-Hyun Nam
Yong Jae Shin
Ichiro Nakano
Wenhao Hu
Dongquan Chen
Peng Cheng
Brendan Frett
Wanfu Xie
Hai Yu
Ahmed Mohyeldin
Mutsuko Minata
Harley I Kornblum
Maode Wang
Violaine Goidts
Hongyu Li
Marat S Pavlyukov
Yeri Lee
Jia Wang
Sung-Hak Kim
Zhuo Zhang
Journal: Journal of Clinical Investigation (2017)
Discipline: CLINICAL MEDICINE
Keywords: Glioma stem cells; NEK2; EZH2; posttranslational regulation; kinase
Affiliations: Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China., Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA., Department of Neurosurgery, The First Hospital, China Medical University, Shenyang, Liaoning, China., Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia., Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, Republic of Korea., Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA., Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA., Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany., Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, USA., Synactix Pharmaceuticals Inc., Tucson, Arizona, USA., Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai, China., Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea., Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea., Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea., Departments of Psychiatry., Pharmacology, and., Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA., Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.

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. 

Retracted: No

PubPeer comments:
 Western blot of NEK2 in Fig 3A and p-EZH2 (Ser21) (Fig 4D) appears to be the same: ![file] NEK2 staining in Fig 3A is weaker (or different) than in merge (yellow circles): ![file] Actually the same first author has used data of this paper in others as already documented here: https: pubpeer.com publications 3EDEE1286A1392F01C7577D8945657 , 
 Universal b-actin loading control, simply flip it: ![file] , 
 Now b-actin turns out to be H3K27me3: ![file] And again a universal b-actin: ![file] , 
 ![file] , 
 2020 expression of concern. https: www.jci.org articles view 142404 The Editors recently became aware of potential blot anomalies in Figures 1J, 2A, 3A, and 4D and Supplemental Figures 3A, 4C, and 6A. The Editors have requested an institutional investigation into this matter, and we will inform our readers of the outcome when the investigation is complete. , 
 2020 retraction. https: www.jci.org articles view 144618 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. ,