Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.

Autor:	Lv D; UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Dixit D; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA., Cruz AF; Brain Tumor Biology and Therapy Lab, Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA., Kim LJY; Division of Regenerative Medicine, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA., Duan L; Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA., Xu X; Princess Margaret Cancer Centre/University Health Network, Toronto, ON, Canada., Wu Q; UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Zhong C; UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Lu C; School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China., Gersey ZC; Brain Tumor Biology and Therapy Lab, Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA., Gimple RC; Division of Regenerative Medicine, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA., Xie Q; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Westlake University, Hangzhou 310024, Zhejiang, China., Yang K; Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA., Liu X; Department of Molecular and Structural Chemistry, North Carolina State University, Raleigh, NC 27695, USA., Fang X; Department of Cancer Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA., Wu X; UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Kidwell RL; Division of Regenerative Medicine, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92037, USA., Wang X; School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China., Bao S; Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA., He HH; Princess Margaret Cancer Centre/University Health Network, Toronto, ON, Canada., Locasale JW; Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA., Agnihotri S; Brain Tumor Biology and Therapy Lab, Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. Electronic address: sameer.agnihotri@gmail.com., Rich JN; UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Division of Regenerative Medicine, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: drjeremyrich@gmail.com.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2024 Nov 05; Vol. 36 (11), pp. 2419-2436.e8. Date of Electronic Publication: 2024 Oct 24.
DOI:	10.1016/j.cmet.2024.09.014
Abstrakt:	Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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