期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 8, 页码 3075-3089出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI89092
关键词
-
资金
- 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 RAMP
- D Project through Korea Health Industry Development Institute (KHIDI)
- Ministry of Health AMP
- Welfare, Republic of Korea [HI14C3418]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据