EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner
Sung-Hak Kim1, Kaushal Joshi1, Ravesanker Ezhilarasan2
1Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
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.
Insights
Glioblastoma stem cells resist radiation therapy through the MELK-FOXM1-EZH2 pathway. Targeting this signaling axis offers a potential therapeutic strategy for recurrent glioblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Stem Cell Biology
Background:
- Glioblastoma (GBM)-derived tumorigenic stem-like cells (GSCs) are implicated in therapy resistance.
- The mitotic kinase MELK was previously shown to bind and phosphorylate the transcription factor FOXM1 in GSCs.
Purpose of the Study:
- To investigate the role of the MELK-FOXM1 complex in GSC radioresistance.
- To identify downstream targets of the MELK-FOXM1 complex involved in radiation resistance.
Main Methods:
- Utilized gain- and loss-of-function studies in GSCs.
- Examined the expression of EZH2, MELK, and FOXM1 in GBM patient samples.
- Investigated the evolutionary conservation of the MELK-EZH2 axis in Caenorhabditis elegans.
Main Results:
- Demonstrated that the MELK-FOXM1 complex targets EZH2, promoting GSC radioresistance.
- Found coexpression of EZH2 and MELK in GBM, with significant induction in postirradiation recurrent tumors.
- Showed that MELK or FOXM1 regulates EZH2 to contribute to GSC radioresistance.
- Confirmed evolutionary conservation of the MELK-EZH2 axis.
Conclusions:
- The MELK-FOXM1-EZH2 signaling axis is crucial for GSC radioresistance.
- This pathway represents a potential therapeutic target for irradiation-resistant GBM.
