R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m(6)A/PFKP/LDHB axis.
R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m(6)A/PFKP/LDHB axis.
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R-2-hydroxyglutarate 通过靶向 FTO/m(6)A/PFKP/LDHB 轴，抑制白血病中的有氧糖酵解。
DOI：
10.1016/j.molcel.2020.12.026
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发表时间：
2021-03-04
期刊：
影响因子：
16
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Qing Y;Dong L;Gao L;Li C;Li Y;Han L;Prince E;Tan B;Deng X;Wetzel C;Shen C;Gao M;Chen Z;Li W;Zhang B;Braas D;Ten Hoeve J;Sanchez GJ;Chen H;Chan LN;Chen CW;Ann D;Jiang L;Müschen M;Marcucci G;Plas DR;Li Z;Su R;Chen J
R-2-羟基戊二酸（R-2HG）是异柠檬酸脱氢酶（IDH）突变体产生的一种代谢产物，具有抗肿瘤活性。然而，它对癌症代谢的影响在很大程度上仍然难以捉摸。在这里，不像它在神经胶质瘤中的ATP合酶的抑制作用，我们显示R-2HG主要减弱有氧糖酵解，癌症代谢的标志，在（R-2HG敏感）白血病细胞。在机制上，R-2HG消除FTO/m6A/YTHDF2介导的PFKP和LDHB（两个关键糖酵解基因）表达的转录后上调，从而抑制有氧糖酵解。FTO、PFKP或LDHB的敲低在（R-2HG敏感的）白血病细胞中重现R-2HG诱导的糖酵解抑制，但在正常的CD 34+造血干/祖细胞中不重现，并且抑制体内白血病发生，而它们的过表达逆转R-2HG诱导的作用。R-2HG还抑制糖酵解并下调人原代IDH-野生型AML细胞中的FTO/PFKP/LDHB表达，证明了临床相关性。总的来说，我们的研究揭示了以前未被认识到的R-2HG和RNA修饰对白血病有氧糖酵解的影响，突出了靶向癌症表位转录组学和代谢的治疗潜力。Qing等人证明，由突变IDH产生的代谢物R-2HG显著抑制敏感（IDH-野生型）白血病细胞中的有氧糖酵解，但不抑制正常造血干/祖细胞中的有氧糖酵解。R-2HG通过靶向FTO/m6A/YTHDF2信号转导下调PFKP和LDHB表达来发挥糖酵解抑制作用，从而有助于其整体抗肿瘤活性。
R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenases (IDH), was recently reported to exhibit anti-tumor activity. However, its effect on cancer metabolism remains largely elusive. Here, unlike its reported inhibitory effect on ATP synthase in glioma, we show R-2HG mainly attenuates aerobic glycolysis, a hallmark of cancer metabolism, in (R-2HG-sensitive) leukemia cells. Mechanistically, R-2HG abrogates FTO/m6A/YTHDF2-mediated post-transcriptional upregulation of PFKP and LDHB (two critical glycolytic genes) expression, and thereby suppresses aerobic glycolysis. Knockdown of FTO, PFKP, or LDHB recapitulates R-2HG-induced glycolytic inhibition in (R-2HG-sensitive) leukemia cells but not normal CD34+ hematopoietic stem/progenitor cells, and inhibits leukemogenesis in vivo, while their overexpression reverses R-2HG-induced effects. R-2HG also suppresses glycolysis and downregulates FTO/PFKP/LDHB expression in human primary IDH-wildtype AML cells, demonstrating the clinical relevance. Collectively, our study reveals previously unrecognized effects of R-2HG and RNA modification on aerobic glycolysis in leukemia, highlighting the therapeutic potential of targeting cancer epitranscriptomics and metabolism. Qing et al. demonstrate that R-2HG, a metabolite produced by mutant IDH, significantly suppresses aerobic glycolysis in sensitive (IDH-wildtype) leukemia cells but not in normal hematopoietic stem/progenitor cells. R-2HG exerts glycolytic inhibitory effects by targeting the FTO/m6A/YTHDF2 signaling to downregulate PFKP and LDHB expression, contributing to its overall anti-tumor activity.
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DOI：
10.1158/1078-0432.ccr-13-0623
发表时间：
2013-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dennison JB;Molina JR;Mitra S;González-Angulo AM;Balko JM;Kuba MG;Sanders ME;Pinto JA;Gómez HL;Arteaga CL;Brown RE;Mills GB
通讯作者：
Mills GB
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
158.5
作者：
DiNardo, C. D.;Stein, E. M.;Kantarjian, H. M.
通讯作者：
Kantarjian, H. M.
影响因子：
56.9
作者：
DAWSON, DM;KAPLAN, NO;GOODFRIEND, TL
通讯作者：
GOODFRIEND, TL
影响因子：
5.4
作者：
Dull, T;Zufferey, R;Naldini, L
通讯作者：
Naldini, L