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 N 6 -methyladenosine

Ist Teil von

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

Ort / Verlag

United States

Erscheinungsjahr

2022

Quelle

MEDLINE

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 N -methyladenosine (m A) 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 m A 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 m A regulation, driving tumor metabolism to promote cancer stem cell maintenance, highlighting PDGF-METTL3-OPTN signaling as a GBM therapeutic target.