2. Academic Validation
  3. PDGF signaling inhibits mitophagy in glioblastoma stem cells through N6-methyladenosine

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

  • Dev Cell. 2022 Jun 20;57(12):1466-1481.e6. doi: 10.1016/j.devcel.2022.05.007.
Deguan Lv 1,  Ryan C Gimple 2,  Cuiqing Zhong 3,  Qiulian Wu 4,  Kailin Yang 5,  Briana C Prager 6,  Bhaskar Godugu 7,  Zhixin Qiu 1,  Linjie Zhao 1,  Guoxin Zhang 8,  Deobrat Dixit 8,  Derrick Lee 1,  Jia Z Shen 9,  Xiqing Li 10,  Qi Xie 11,  Xiuxing Wang 12,  Sameer Agnihotri 13,  Jeremy N Rich 14
Affiliations

Affiliations

  • 1 Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA.
  • 2 Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
  • 3 Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA 92037, USA.
  • 4 Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
  • 5 Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 6 Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
  • 7 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  • 8 Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA.
  • 9 Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA.
  • 10 Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; Department of Oncology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan 450003, China.
  • 11 Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang 310024, China.
  • 12 Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
  • 13 Department of Neurological Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
  • 14 Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA. Electronic address: [email protected].
PMID: 35659339 DOI: 10.1016/j.devcel.2022.05.007
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 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.

Keywords

(m(6)A); METTL3; N6-methyladenosine; OPTN; PDGF; PDGFRβ; cancer stem cell; glioblastoma; glioblastoma stem cell; mitophagy; optineurin.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-134673
    99.88%, METTL3 Inhibitor