EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner.

in Stem cell reports by 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

TLDR

  • The study investigates how certain cells in the brain called GSCs become resistant to radiation therapy. The researchers found that a protein called MELK helps these cells become resistant by binding to another protein called FOXM1 and targeting a protein called EZH2. The study also shows that these proteins are often found together in brain tumors and that increasing their levels can be linked to a worse outcome for patients. The researchers suggest that targeting this pathway could be a new way to treat brain tumors that are resistant to radiation therapy.

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.

Overview

  • The study investigates the role of GSCs in therapy resistance in GBM. The authors report that the mitotic kinase MELK binds and phosphorylates the oncogenic transcription factor FOXM1 in GSCs. The study then demonstrates that the catalytic subunit of Polycomb repressive complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which promotes resistance to radiation in GSCs. The study also shows that 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, the authors show that MELK or FOXM1 contributes to GSC radioresistance by regulation of EZH2. The study also demonstrates that the MELK-EZH2 axis is evolutionarily conserved in Caenorhabditis elegans. The primary objective of the study is to understand the mechanisms underlying GSC radioresistance and identify potential therapeutic targets for irradiation-resistant GBM tumors.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions. The authors found that the mitotic kinase MELK binds and phosphorylates the oncogenic transcription factor FOXM1 in GSCs. The study then demonstrates that the catalytic subunit of Polycomb repressive complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which promotes resistance to radiation in GSCs. The study also shows that 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, the authors show that MELK or FOXM1 contributes to GSC radioresistance by regulation of EZH2. The study also demonstrates that the MELK-EZH2 axis is evolutionarily conserved in Caenorhabditis elegans. The key findings of the study 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.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study identifies the MELK-FOXM1-EZH2 signaling axis as a potential therapeutic target for irradiation-resistant GBM tumors. The study also highlights the importance of understanding the mechanisms underlying GSC radioresistance and identifying potential therapeutic targets for GBM. The study's limitations include the use of in vitro models and the need for further validation in vivo. Future research directions could include the development of targeted therapies against the MELK-FOXM1-EZH2 signaling axis and the investigation of the role of GSCs in GBM progression and treatment response.
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