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.

中文翻译：

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苹果酸脱氢酶 2 对胶质母细胞瘤干细胞表观转录组的代谢调控


肿瘤对其新陈代谢进行重新编程以产生复杂的肿瘤生态系统。在这里，我们证明胶质母细胞瘤 （GBM） 干细胞 （GSC） 表现出苹果酸-天冬氨酸穿梭 （MAS） 活性升高和苹果酸脱氢酶 2 （MDH2） 的表达。MDH2 的遗传和药理学靶向减弱了 GSC 增殖、自我更新和 体内肿瘤生长，部分被天冬氨酸挽救。靶向 MDH2 诱导 α-酮戊二酸 （αKG） 的积累，αKG 是双加氧酶的关键辅助因子，包括 N6-甲基腺苷 （m6A） RNA 脱甲基酶 AlkB 同源物 5、RNA 脱甲基酶 （ALKBH5）。MDH2 的强制表达增加了 m6A 水平并抑制了 ALKBH5 活性，两者都被 αKG 补充剂挽救。反过来，靶向 MDH2 降低了血小板衍生生长因子受体-β （PDGFRβ） 作为调节转录物的整体 m6A 水平。GSC 中 MDH2 的药理学抑制增强了达沙替尼的疗效，达沙替尼是一种口服生物可利用的多激酶抑制剂，包括 PDGFRβ。总的来说，干细胞样肿瘤细胞对其新陈代谢进行重编程，以诱导其表观转录组的变化并揭示可能的治疗范式。