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

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

SUBMITTER: Lv D 

PROVIDER: S-EPMC11726586 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature