title: EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner.
abstract: Glioblastoma (GBM)-derived tumorigenic stem-like cells (GSCs) may play a key role in therapy resistance. Previously, we reported that the mitotic kinase MELK binds and phosphorylates the oncogenic transcription factor FOXM1 in GSCs. Here, we demonstrate that the catalytic subunit of Polycomb repressive complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which in turn promotes resistance to radiation in GSCs. Clinically, EZH2 and MELK are coexpressed in GBM and significantly induced in postirradiation recurrent tumors whose expression is inversely correlated with patient prognosis. Through a gain-and loss-of-function study, we show that MELK or FOXM1 contributes to GSC radioresistance by regulation of EZH2. We further demonstrate that the MELK-EZH2 axis is evolutionarily conserved in Caenorhabditis elegans. Collectively, these data suggest that the MELK-FOXM1-EZH2 signaling axis is essential for GSC radioresistance and therefore raise the possibility that MELK-FOXM1-driven EZH2 signaling can serve as a therapeutic target in irradiation-resistant GBM tumors.
authors.affiliation: Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kaushal
authors.initials: K
authors.lastname: Joshi
authors.affiliation: Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ravesanker
authors.initials: R
authors.lastname: Ezhilarasan
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
authors.forename: Toshia R
authors.initials: TR
authors.lastname: Myers
authors.affiliation: Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Siu
authors.affiliation: Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Mariko
authors.initials: M
authors.lastname: Nakano-Okuno
authors.affiliation: Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: David
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Minata
authors.affiliation: Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jeongwu
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Krishna P L
authors.initials: KP
authors.lastname: Bhat
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
authors.forename: Anna Elisabetta
authors.initials: AE
authors.lastname: Salcini
authors.affiliation: Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. Electronic address: ichiro.nakano@osumc.edu.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000528:radiation effects; D004195:Disease Models, Animal; D000071221:Enhancer of Zeste Homolog 2 Protein; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D064593:Heterografts; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000528:radiation effects*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases