PDGF signaling inhibits mitophagy in glioblastoma stem cells through N 6 -methyladenosine

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

doi:10.1016/j.devcel.2022.05.007

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PDGF signaling inhibits mitophagy in glioblastoma stem cells through N 6 -methyladenosine

Journal article

Open access

Peer reviewed

PDGF signaling inhibits mitophagy in glioblastoma stem cells through N 6 -methyladenosine

Deguan Lv, Ryan C Gimple, Cuiqing Zhong, Qiulian Wu, Kailin Yang, Briana C Prager, Bhaskar Godugu, Zhixin Qiu, Linjie Zhao, Guoxin Zhang, …

Developmental cell, Vol.57(12), p.1466

06/20/2022

DOI: 10.1016/j.devcel.2022.05.007

PMCID: PMC9239307

PMID: 35659339

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Abstract

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.

Adenosine - analogs & derivatives

Brain Neoplasms - metabolism

Cell Line, Tumor

Gene Expression Regulation, Neoplastic

Glioblastoma - genetics

Glioblastoma - metabolism

Glioblastoma - pathology

Humans

Methyltransferases - metabolism

Mitophagy

Neoplastic Stem Cells - pathology

Platelet-Derived Growth Factor - metabolism

Platelet-Derived Growth Factor - pharmacology

Details

Title: Subtitle: PDGF signaling inhibits mitophagy in glioblastoma stem cells through N 6 -methyladenosine
Creators: Deguan Lv - University of California San Diego
Ryan C Gimple - University of California San Diego
Cuiqing Zhong - Salk Institute for Biological Studies
Qiulian Wu - University of Pittsburgh Medical Center
Kailin Yang - Cleveland Clinic
Briana C Prager - Cleveland Clinic Lerner College of Medicine
Bhaskar Godugu - University of Pittsburgh
Zhixin Qiu - University of California San Diego
Linjie Zhao - University of California San Diego
Guoxin Zhang - University of California San Diego
Deobrat Dixit - University of California San Diego
Derrick Lee - UPMC Hillman Cancer Center
Jia Z Shen - Sanford Burnham Prebys Medical Discovery Institute
Xiqing Li - University of California San Diego
Qi Xie - University of California San Diego
Xiuxing Wang - University of California San Diego
Sameer Agnihotri - Children's Hospital of Pittsburgh
Jeremy N Rich - University of California San Diego
Resource Type: Journal article
Publication Details: Developmental cell, Vol.57(12), p.1466
DOI: 10.1016/j.devcel.2022.05.007
PMID: 35659339
PMCID: PMC9239307
NLM abbreviation: Dev Cell
ISSN: 1534-5807
eISSN: 1878-1551
Grant note: F30 CA217066 / NCI NIH HHS F30 CA217065 / NCI NIH HHS T32 CA094186 / NCI NIH HHS R35 CA197718 / NCI NIH HHS R01 CA238662 / NCI NIH HHS R01 NS103434 / NINDS NIH HHS R01 NS115831 / NINDS NIH HHS
Language: English
Date published: 06/20/2022
Academic Unit: Radiation Oncology
Record Identifier: 9984696578002771

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