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

Abstract

SummaryGlioblastoma (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.

Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2

“…In a previous study, we demonstrated that the radioresistance of GBM tumors depends on MELK-mediated EZH2 signaling in GSCs (24). The MELK kinase inhibitor OTS167 is currently being tested in a phase I clinical trial for solid nonbrain cancers (https://clinicaltrials.gov/ct2/show/NCT01910545?term= OTS167&rank=1).…”

“…We also found that EZH2-mediated GSC maintenance and the radiation resistance of GSCs depend on maternal embryonic leucine zipper kinase (MELK) by its protein complex formation with the transcription factor FOXM1 (24). These studies led us to speculate that the MELK/EZH2/STAT3 signaling axis is a central regulator for GSC tumorigenicity in GBM.…”

Cancer stem cells in glioblastoma

“…The addition of TMZ to radiation has increased median survival by several months (Stupp et al 2009), but lineage tracing studies in mouse models demonstrate that CSCs repopulate brain tumors after TMZ treatment . A number of molecular mechanisms have been identified that mediate the therapeutic resistance of CSCs to cytotoxic therapies, including the DNA damage checkpoint, Notch, NF-κB, EZH2, and PARP (Bao et al 2006a;Wang et al 2010;Bhat et al 2013;Venere et al 2014;Kim et al 2015), which suggests that CSCs develop multiple mechanisms of resistance that may require combinations of targeted agents. Moving forward, these studies demonstrate the importance of understanding the molecular alterations that are present in recurrent tumors and how these influence the structure of cells within the tumor hierarchy.…”

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

“…In terms of glioblastoma, inactivated ALKBH5 inhibited the proliferation and tumorigenesis of GSCs and impaired GSCs self‐renewal 75. It is widely accepted that FOXM1 plays a pivotal role in regulating GSCs proliferation and self‐renewal 76, 77. ALKBH5 was found to demethylate FOXM1 nascent transcripts and promote FOXM1 expression, whereas long non‐coding RNA antisense of FOXM1 further promoted the interaction of FOXM1 nascent transcripts with ALKBH5.…”