A tumor suppressor role for EZH2 in diffuse midline glioma pathogenesis

Swati Dhar, Samantha Gadd, Priyam Patel, Jake Vaynshteyn, G. Praveen Raju, Rintaro Hashizume, Daniel J. Brat, Oren Josh Becher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Pediatric high-grade gliomas, specifically diffuse midline gliomas, account for only 20% of clinical cases but are 100% fatal. A majority of the DMG cases are characterized by the signature K27M mutation in histone H3. The H3K27M mutation opposes the function of enhancer of zeste homolog 2 (EZH2), the methyltransferase enzyme of the polycomb repressor complex 2. However, the role of EZH2 in DMG pathogenesis is unclear. In this study, we demonstrate a tumor suppressor function for EZH2 using Ezh2 loss- and gain-of-function studies in H3WT DMG mouse models. Genetic ablation of Ezh2 increased cell proliferation and tumor grade while expression of an Ezh2 gain-of-function mutation significantly reduced tumor incidence and increased tumor latency. Transcriptomic analysis revealed that Ezh2 deletion upregulates an inflammatory response with upregulation of immunoproteasome genes such as Psmb8, Psmb9, and Psmb10. Ezh2 gain-of-function resulted in 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 7-day treatment of H3K27M DMG tumor bearing mice with an EZH2 inhibitor, Tazemetostat, did not alter proliferation or significantly impact survival. Together our results suggest that EZH2 has a tumor suppressor function in DMG and warrants caution in clinical translation of EZH2 inhibitors to treat patients with DMG.

Original languageEnglish (US)
Article number47
JournalActa Neuropathologica Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • Diffuse midline gliomas (DMGs)
  • Ezh2 gain-of-function
  • Ezh2 loss-of-function
  • Interferon gamma
  • Oxidative phosphorylation
  • Tumor suppressor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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