A tumor suppression role for EZH2 in Diffuse Intrinsic Pontine Glioma pathogenesis

ABSTRACT: Pediatric high-grade gliomas, specifically diffuse intrinsic pontine gliomas (DIPG), account for 20% of clinical cases but have a 100% fatality rate. A majority of DIPG cases are characterized by the signature H3K27M mutation that is predicted to oppose EZH2, the methyltransferase enzyme of the Polycomb Repressor Complex 2 (PRC2). However, a clear understanding of EZH2’s role in DIPG is lacking. In this study, by incorporating Ezh2 loss and gain of function into our DIPG mouse models we demonstrate its tumor suppressor function. Genetic ablation of Ezh2 increased cell proliferation and tumor grade while expression of an Ezh2 gain of function mutation significantly reduced tumor incidence, increased tumor latency. Transcriptomic analysis revealed that EZH2 deletion upregulates an inflammatory response with upregulation of immunoproteasome genes such as Psmb8, Psmb9, and Psmb10 while EZH2 deletion an enrichment of the oxidative phosphorylation/mitochondrial metabolic pathway namely the isocitrate dehydrogenase Idh1/2/3 genes. Pharmacological inhibition of EZH2 augmented neural progenitor cell proliferation, supporting the tumor suppressive role of EZH2. In vivo treatment of DIPG tumor bearing Ntv-a;p53fl/fl; abcb1a-/-; abcb1b-/-; abcg2-/- (ABC knockout, ABC KO) mice with EZH2 inhibitor, EPZ-6438 did not alter proliferation or significantly impact survival. Together our results suggest that EZH2 has a tumor suppressor function in DIPG and warrants caution in clinical translation of these inhibitors to treat patients with DIPG.

ORGANISM(S): Mus musculus

PROVIDER: GSE188450 | GEO | 2022/01/01

REPOSITORIES: GEO