Journal article
Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2
Cell metabolism, Vol.36(11), pp.2419-2436.e8
10/19/2024
DOI: 10.1016/j.cmet.2024.09.014
PMCID: PMC11726586
PMID: 39454581
Abstract
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.
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•GSCs exhibit high activity of the malate-aspartate shuttle (MAS)•Targeting malate dehydrogenase 2 (MDH2) reduces GSC proliferation and stemness•MDH2 regulates m6A modifications of PDGFRB mRNA via αKG-dependent ALKBH5 inhibition•MDH2 inhibition augments the efficacy of dasatinib against GSCs
Lv et al. find that stem-like tumor cells preferentially activate the malate-aspartate shuttle (MAS), which represses levels of α-ketoglutarate, a metabolite co-factor for the mRNA demethylase ALKBH5, to reprogram the epitranscriptome and maintain tumor stemness. Targeting this tumor-associated metabolic pathway through malate dehydrogenase 2 sensitizes highly resistant cancer cells to targeted therapeutics. Collectively, tumors reprogram their metabolic states to promote RNA diversity and maintenance of cancer stem cells, providing therapeutic vulnerabilities.
Details
- Title: Subtitle
- Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2
- Creators
- Leo J.Y. Kim - Case Western Reserve UniversityLikun Duan - Duke UniversityXin Xu - Princess Margaret Cancer CentreQiulian Wu - University of Pittsburgh Medical CenterCuiqing Zhong - University of Pittsburgh Medical CenterChenfei Lu - Nanjing Medical UniversityZachary C. Gersey - University of Pittsburgh Medical CenterRyan C. Gimple - University of California San DiegoQi Xie - Westlake UniversityKailin Yang - Cleveland ClinicXiaojing Liu - North Carolina State UniversityXiaoguang Fang - Cleveland ClinicXujia Wu - University of Pittsburgh Medical CenterReilly L. Kidwell - University of California San DiegoXiuxing Wang - Nanjing Medical UniversityShideng Bao - Cleveland ClinicHousheng H. He - Princess Margaret Cancer CentreDeguan Lv - University of Pittsburgh Medical CenterJason W. Locasale - Duke UniversityDeobrat Dixit - Columbia University Irving Medical CenterSameer Agnihotri - University of Pittsburgh Medical CenterJeremy N. Rich - University of Pittsburgh Medical CenterAndrea F. Cruz - University of Pittsburgh Medical Center
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.36(11), pp.2419-2436.e8
- DOI
- 10.1016/j.cmet.2024.09.014
- PMID
- 39454581
- PMCID
- PMC11726586
- NLM abbreviation
- Cell Metab
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Publisher
- Elsevier Inc
- Grant note
- National Institutes of Health: CA217065, CA203101, CA197718, CA238662, CA268634, NS136424, NS103434 American Cancer Society Lisa Dean Mose-ley Foundation Cancer Stem Cell ConsortiumUS Army DOD: CA220598 ChadTough DefeatDIPG Foundation fellowship award
We appreciate the members of the Rich laboratory and Agnihotri laboratory for critical inputs and helpful discussions. We appreciate the various core facilities at UCSD and UPMC for their work on experiments and analysis. Finally, we would like to thank our funding sources: The National Institutes of Health grants CA217065 (R.C.G.) ; CA203101 (L.J.Y.K.) ; CA197718, CA238662, CA268634, NS136424, and NS103434 (J.N.R.) ; and CA268634 (S.A. and J.N.R.) . J.N.R. is supported by the American Cancer Society Lisa Dean Moseley Foundation Cancer Stem Cell Consortium and the US Army DOD (CA220598) . A.F.C. is supported by the ChadTough DefeatDIPG Foundation fellowship award.
- Language
- English
- Date published
- 10/19/2024
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984740853602771
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