TY - JOUR 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, Hongyu AU - Shin, Yong Jae AU - Lee, Yeri AU - Nam, Do-Hyun AU - Kornblum, Harley I. AU - Wang, Maode AU - Nakano, Ichiro T1 - Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2 PY - 2017/08/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI89092 VL - 127 IS - 8 UR - https://doi.org/10.1172/JCI89092 SP - 3075 EP - 3089 PB - The American Society for Clinical Investigation ER -