Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2
Pavlyukov, Marat S.
Shin, Yong Jae
Kornblum, Harley I.
AffiliationUniv Arizona, Dept Pharmacol & Toxicol
MetadataShow full item record
PublisherAMER SOC CLINICAL INVESTIGATION INC
CitationTargeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2 2017, 127 (8):3075 Journal of Clinical Investigation
RightsCopyright © 2017, American Society for Clinical Investigation.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractAccumulating 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.
NoteAuthors retain rights to present the work without prior permission in original, revised, adapted, or derivative form, provided that all such use is for personal or nonprofit (and noncommercial) benefit, is consistent with any employment agreement, and references the original publication citation. Examples: reproduction in nonprofit publications; lecture display (slides, overheads, or digitized media); hosting on personal or curriculum vitae-oriented websites; and inclusion in institutional and/or funding-body repositories.
VersionFinal published version
SponsorsNIH [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 R&D Project through Korea Health Industry Development Institute (KHIDI); Ministry of Health & Welfare, Republic of Korea [HI14C3418]
- EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner.
- Authors: Kim SH, Joshi K, Ezhilarasan R, Myers TR, Siu J, Gu C, Nakano-Okuno M, Taylor D, Minata M, Sulman EP, Lee J, Bhat KP, Salcini AE, Nakano I
- Issue date: 2015 Feb 10
- Melatonin inhibits tumorigenicity of glioblastoma stem-like cells via the AKT-EZH2-STAT3 signaling axis.
- Authors: Chen X, Hao A, Li X, Du Z, Li H, Wang H, Yang H, Fang Z
- Issue date: 2016 Sep
- EZH2 interacts with HP1BP3 to epigenetically activate WNT7B that promotes temozolomide resistance in glioblastoma.
- Authors: Yu T, Zhou F, Tian W, Xu R, Wang B, Zeng A, Zhou Z, Li M, Wang Y, Zhang J
- Issue date: 2023 Feb
- Dissecting the role of novel EZH2 inhibitors in primary glioblastoma cell cultures: effects on proliferation, epithelial-mesenchymal transition, migration, and on the pro-inflammatory phenotype.
- Authors: Stazi G, Taglieri L, Nicolai A, Romanelli A, Fioravanti R, Morrone S, Sabatino M, Ragno R, Taurone S, Nebbioso M, Carletti R, Artico M, Valente S, Scarpa S, Mai A
- Issue date: 2019 Dec 2
- Enhancer of Zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells.
- Authors: Orzan F, Pellegatta S, Poliani PL, Pisati F, Caldera V, Menghi F, Kapetis D, Marras C, Schiffer D, Finocchiaro G
- Issue date: 2011 Jun