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PDGF signaling inhibits mitophagy in glioblastoma stem cells through N 6 -methyladenosine.
- Source :
-
Developmental cell [Dev Cell] 2022 Jun 20; Vol. 57 (12), pp. 1466-1481.e6. Date of Electronic Publication: 2022 Jun 03. - Publication Year :
- 2022
-
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 <superscript>6</superscript> -methyladenosine (m <superscript>6</superscript> 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 <superscript>6</superscript> 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 <superscript>6</superscript> A regulation, driving tumor metabolism to promote cancer stem cell maintenance, highlighting PDGF-METTL3-OPTN signaling as a GBM therapeutic target.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Subjects :
- Adenosine analogs & derivatives
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
Methyltransferases metabolism
Mitophagy
Neoplastic Stem Cells pathology
Platelet-Derived Growth Factor metabolism
Platelet-Derived Growth Factor pharmacology
Brain Neoplasms metabolism
Glioblastoma genetics
Glioblastoma metabolism
Glioblastoma pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1551
- Volume :
- 57
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Developmental cell
- Publication Type :
- Academic Journal
- Accession number :
- 35659339
- Full Text :
- https://doi.org/10.1016/j.devcel.2022.05.007