PDGF Signaling Promotes Mitophagy in Glioblastoma Stem Cells Through N 6 -Methyladenosine

Glioblastomas are lethal primary brain tumors that contain glioblastoma stem cells (GSCs) that promote tumor growth. N6-methyladenosine (m6A) is the most common internal modification of mRNA and maintains critical GSC phenotypes. Here, we interrogated upstream regulation of m6A modifications in GSCs, revealing platelet-derived growth factor (PDGF) induction of m6A levels mediated by the methyltransferase METTL3. PDGF signaling stimulated EGR1 transcription that induced METTL3 to promote GSC proliferation and self-renewal, while targeting the PDGF-METTL3 axis generated mitochondrial dysfunction via mitophagy inhibition by regulating mRNA of the mitophagy regulator optineurin (OPTN) through m6A modification. Forced OPTN expression phenocopied PDGF inhibition and OPTN levels portend longer survival of glioblastoma patients. Collectively, we describe novel upstream regulation of m6A manifesting in mitochondrial regulation to promote maintenance of GSC stemness and proliferation, highlighting PDGF-METTL3-OPTN signaling as a therapeutic target in glioblastoma.