Details

Autor(en) / Beteiligte

• Lv, Deguan
• Gimple, Ryan C.
• Zhong, Cuiqing
• Wu, Qiulian
• Yang, Kailin
• Prager, Briana C.
• Godugu, Bhaskar
• Qiu, Zhixin
• Zhao, Linjie
• Zhang, Guoxin
• Dixit, Deobrat
• Lee, Derrick
• Shen, Jia Z.
• Li, Xiqing
• Xie, Qi
• Wang, Xiuxing
• Agnihotri, Sameer
• Rich, Jeremy N.

Titel

PDGF signaling inhibits mitophagy in glioblastoma stem cells through N6-methyladenosine

Ist Teil von

• Developmental cell, 2022-06, Vol.57 (12), p.1466-1481.e6

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2022

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Dysregulated growth factor receptor pathways, RNA modifications, and metabolism each promote tumor heterogeneity. Here, we demonstrate that platelet-derived growth factor (PDGF) signaling induces N6-methyladenosine (m6A) accumulation in glioblastoma (GBM) stem cells (GSCs) to regulate mitophagy. PDGF ligands stimulate early growth response 1 (EGR1) transcription to induce methyltransferase-like 3 (METTL3) to promote GSC proliferation and self-renewal. Targeting the PDGF-METTL3 axis inhibits mitophagy by regulating m6A modification of optineurin (OPTN). Forced OPTN expression phenocopies PDGF inhibition, and OPTN levels portend longer survival of GBM patients; these results suggest a tumor-suppressive role for OPTN. Pharmacologic targeting of METTL3 augments anti-tumor efficacy of PDGF receptor (PDGFR) and mitophagy inhibitors in vitro and in vivo. Collectively, we define PDGF signaling as an upstream regulator of oncogenic m6A regulation, driving tumor metabolism to promote cancer stem cell maintenance, highlighting PDGF-METTL3-OPTN signaling as a GBM therapeutic target. [Display omitted] •PDGF signaling upregulates m6A levels in GBM through the transcriptional control of METTL3•PDGF-METTL3 represses OPTN by m6A modification to inhibit GSC mitophagy•OPTN inhibits GBM tumor growth in vitro and in vivo•Pharmacologic METTL3 inhibition synergizes with PDGFR and mitophagy inhibitors Lv et al. interrogate the upstream regulation of global N6-methyladenosine (m6A) levels in glioblastoma stem cells (GSCs). PDGFR upregulates the methyltransferase METTL3 to induce m6A modifications, including on OPTN to regulate mitophagy, revealing therapeutic combinations against GSCs.