EZH2 Protects Glioma Stem Cells from Radiation-Induced Cell Death in a MELK/FOXM1-Dependent Manner

Sung-Hak Kim; Kaushal Joshi; Ravesanker Ezhilarasan; Toshia R Myers; Jason Siu; Chunyu Gu; Mariko Nakano-Okuno; David Taylor; Mutsuko Minata; Erik P Sulman; Jeongwu Lee; Krishna P L Bhat; Anna Elisabetta Salcini; Ichiro Nakano

doi:10.1016/j.stemcr.2014.12.006

EZH2 Protects Glioma Stem Cells from Radiation-Induced Cell Death in a MELK/FOXM1-Dependent Manner

Sung-Hak Kim, Kaushal Joshi, Ravesanker Ezhilarasan, Toshia R Myers, Jason Siu, Chunyu Gu, Mariko Nakano-Okuno, David Taylor, Mutsuko Minata, Erik P Sulman, Jeongwu Lee, Krishna P L Bhat, Anna Elisabetta Salcini, Ichiro Nakano

106 Citations (Scopus)

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.

Original language	English
Journal	Stem Cell Reports
ISSN	2213-6711
DOIs	https://doi.org/10.1016/j.stemcr.2014.12.006
Publication status	Published - 10 Feb 2015

Access to Document

10.1016/j.stemcr.2014.12.006

Cite this

@article{4ac443dad5df4d0a9144a20be8f0e8c0,

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.",

author = "Sung-Hak Kim and Kaushal Joshi and Ravesanker Ezhilarasan and Myers, {Toshia R} and Jason Siu and Chunyu Gu and Mariko Nakano-Okuno and David Taylor and Mutsuko Minata and Sulman, {Erik P} and Jeongwu Lee and Bhat, {Krishna P L} and Salcini, {Anna Elisabetta} and Ichiro Nakano",

year = "2015",

month = feb,

day = "10",

doi = "10.1016/j.stemcr.2014.12.006",

language = "English",

journal = "Stem Cell Reports",

issn = "2213-6711",

publisher = "Cell Press",

}

TY - JOUR

T1 - EZH2 Protects Glioma Stem Cells from Radiation-Induced Cell Death in a MELK/FOXM1-Dependent Manner

AU - Kim, Sung-Hak

AU - Joshi, Kaushal

AU - Ezhilarasan, Ravesanker

AU - Myers, Toshia R

AU - Siu, Jason

AU - Gu, Chunyu

AU - Nakano-Okuno, Mariko

AU - Taylor, David

AU - Minata, Mutsuko

AU - Sulman, Erik P

AU - Lee, Jeongwu

AU - Bhat, Krishna P L

AU - Salcini, Anna Elisabetta

AU - Nakano, Ichiro

PY - 2015/2/10

Y1 - 2015/2/10

N2 - 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.

AB - 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.

U2 - 10.1016/j.stemcr.2014.12.006

DO - 10.1016/j.stemcr.2014.12.006

M3 - Journal article

C2 - 25601206

SN - 2213-6711

JO - Stem Cell Reports

JF - Stem Cell Reports

ER -

EZH2 Protects Glioma Stem Cells from Radiation-Induced Cell Death in a MELK/FOXM1-Dependent Manner

Abstract

Access to Document

Fingerprint

Cite this