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PDGF signaling inhibits mitophagy in glioblastoma stem cells through N6-methyladenosine.
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.
Afiliación
  • Lv D; 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.
  • Gimple RC; 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.
  • Zhong C; 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.
  • Wu Q; Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
  • Yang K; Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
  • Prager BC; 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.
  • Godugu B; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  • Qiu Z; 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.
  • Zhao L; 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.
  • Zhang G; Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA.
  • Dixit D; Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA.
  • Lee D; 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.
  • Shen JZ; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA.
  • Li X; 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.
  • Xie Q; 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.
  • Wang X; 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.
  • Agnihotri S; Department of Neurological Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
  • Rich JN; 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. Electr
Dev Cell ; 57(12): 1466-1481.e6, 2022 06 20.
Article en En | MEDLINE | ID: mdl-35659339
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Glioblastoma Límite: Humans Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Glioblastoma Límite: Humans Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos