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

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

The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma

Glioblastomas are responsible for nearly 60% of malignant primary brain tumors. Those with a mesenchymal (MES) gene expression signature present with worse survival and increased treatment resistance. Performing an extensive gene network analysis, Bhat et al. now identify the TAZ transcriptional coactivator as a master modulator of this severe MES signature. Validating their bioinformatic analysis in patient-derived glioma stem cells and murine neural stem cells, they further observe that TAZ expression is restrained in lower-grade gliomas due to promoter hypermethylation and that TAZ regulates MES genes by directly binding their promoters in complex with TEAD2. This study reveals a direct role for TAZ in driving MES differentiation in malignant gliomas

Mesenchymal Differentiation Mediated by NF-kappa B Promotes Radiation Resistance in Glioblastoma

<p>Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or nnesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-alpha/NF-kappa B-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macrophages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-kappa B activation correlate with poor radiation response and shorter survival in patients with GBM.</p>