美国匹兹堡大学医学中心Jeremy N. Rich和Sameer Agnihotri共同合作，近期取得重要工作进展，他们研究提出了苹果酸脱氢酶2对胶质母细胞瘤干细胞表观转录组的代谢调控。相关研究成果2024年10月24日在线发表于《细胞—代谢》杂志发上。

据介绍，肿瘤重新编程其代谢以产生复杂的肿瘤生态系统。

研究人员证明，胶质母细胞瘤（GBM）干细胞（GSC）显示出苹果酸-天冬氨酸穿梭（MAS）活性和苹果酸脱氢酶2（MDH2）表达升高。MDH2的遗传和药理学靶向减弱了GSC的增殖、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因子，包括N6甲基腺苷（m6A）RNA脱甲基酶AlkB同源物5、RNA去甲基化酶（ALKBH5）。

MDH2的强制表达增加了m6A水平并抑制了ALKBH5活性，这两者都可以通过补充αKG来挽救。反过来，靶向MDH2降低了血小板来源生长因子受体β（PDGFRβ）作为受调节转录物的整体m6A水平。GSC中MDH2的药理学抑制增强了达沙替尼（一种口服生物可利用的多激酶抑制剂，包括PDGFRβ）的疗效。

总之，干细胞样肿瘤细胞对其代谢进行重新编程，以诱导其表观转录组的变化，并揭示可能的治疗模式。

附：英文原文

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

Author: Deguan Lv, Deobrat Dixit, Andrea F. Cruz, Leo J.Y. Kim, Likun Duan, Xin Xu, Qiulian Wu, Cuiqing Zhong, Chenfei Lu, Zachary C. Gersey, Ryan C. Gimple, Qi Xie, Kailin Yang, Xiaojing Liu, Xiaoguang Fang, Xujia Wu, Reilly L. Kidwell, Xiuxing Wang, Shideng Bao, Housheng H. He, Jason W. Locasale, Sameer Agnihotri, Jeremy N. Rich

Issue&Volume: 2024-10-24

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.

DOI: 10.1016/j.cmet.2024.09.014

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00396-6