@article{a7ed94d92f6a40eca83e3b638df18151,
title = "R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis",
abstract = "R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenases (IDHs), was recently reported to exhibit anti-tumor activity. However, its effect on cancer metabolism remains largely elusive. Here we show that R-2HG effectively attenuates aerobic glycolysis, a hallmark of cancer metabolism, in (R-2HG-sensitive) leukemia cells. Mechanistically, R-2HG abrogates fat-mass- and obesity-associated protein (FTO)/N6-methyladenosine (m6A)/YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated post-transcriptional upregulation of phosphofructokinase platelet (PFKP) and lactate dehydrogenase B (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 in normal CD34+ hematopoietic stem/progenitor cells, and inhibits leukemogenesis in vivo; conversely, their overexpression reverses R-2HG-induced effects. R-2HG also suppresses glycolysis and downregulates FTO/PFKP/LDHB expression in human primary IDH-wild-type acute myeloid leukemia (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-wild-type) 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.",
keywords = "FTO, LDHB, N-methyladenosine (mA) modification, PFKP, R-2HG, RNA stability, YTHDF2, cancer metabolism, glycolysis, leukemia",
author = "Ying Qing and Lei Dong and Lei Gao and Chenying Li and Yangchan Li and Li Han and Emily Prince and Brandon Tan and Xiaolan Deng and Collin Wetzel and Chao Shen and Min Gao and Zhenhua Chen and Wei Li and Bin Zhang and Daniel Braas and {ten Hoeve}, Johanna and Sanchez, {Gerardo Javier} and Huiying Chen and Chan, {Lai N.} and Chen, {Chun Wei} and David Ann and Lei Jiang and Markus M{\"u}schen and Guido Marcucci and Plas, {David R.} and Zejuan Li and Rui Su and Jianjun Chen",
note = "Funding Information: We thank Jenna Minami for LC-MS data processing and quality control and thank Atsuo T. Sasaki for providing plasmids. This work was supported in part by the National Institutes of Health (NIH) grants R01 CA243386 (J.C.), R01 CA214965 (J.C.), R01 CA236399 (J.C.), R01 CA211614 (J.C.), R01 DK124116 (J.C.); The Margaret Early Medical Research Trust (R.S.); and The Held Foundation Fellowship (Y.Q.), R35 CA197628 (M.M.), U10 CA180827 (M.M.), R01 CA137060 (M.M.), R01 CA157644 (M.M.), R01 CA172558 (M.M.), and R01 CA213138 (M.M.). J.C. is a Leukemia and Lymphoma Society (LLS) Scholar. Z.L. is an American Cancer Society (ACS) Research Scholar. M.M. is a Howard Hughes Medical Institute (HHMI) Faculty Scholar. B.T. is an American Association for Cancer Research (AACR) Breast Cancer Research Postdoc Fellow. Funding Information: We thank Jenna Minami for LC-MS data processing and quality control and thank Atsuo T. Sasaki for providing plasmids. This work was supported in part by the National Institutes of Health (NIH) grants R01 CA243386 (J.C.), R01 CA214965 (J.C.), R01 CA236399 (J.C.), R01 CA211614 (J.C.), R01 DK124116 (J.C.); The Margaret Early Medical Research Trust (R.S.); and The Held Foundation Fellowship (Y.Q.), R35 CA197628 (M.M.), U10 CA180827 (M.M.), R01 CA137060 (M.M.), R01 CA157644 (M.M.), R01 CA172558 (M.M.), and R01 CA213138 (M.M.). J.C. is a Leukemia and Lymphoma Society (LLS) Scholar. Z.L. is an American Cancer Society (ACS) Research Scholar. M.M. is a Howard Hughes Medical Institute (HHMI) Faculty Scholar. B.T. is an American Association for Cancer Research (AACR) Breast Cancer Research Postdoc Fellow. Conceptualization, Y.Q. R.S. and J.C.; Supervision, R.S. and J.C.; Formal Analysis, L.D. D.B. and G.J.S.; Investigation, Y.Q. L.D. L.G. C.L.Y.L. L.H. E.P. B.T. X.D. C.W. C.S. M.G. Z.C. W.L. D.B. J.t.H. G.J.S. H.C. L.N.C. D.R.P. R.S. and J.C.; Resources, Y.Q. B.T. B.Z. D.B. J.t.H. C.-W.C. D.A. L.J. G.M. D.R.P. Z.L. R.S. and J.C.; Funding Acquisition, Y.Q. M.M. R.S. and J.C.; Writing?Original Draft, Y.Q.; Writing?Review and Editing, Y.Q. L.G. R.S. and J.C. J.C. is a scientific founder of Genovel Biotech Corp. and holds equities with the company. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = mar,
day = "4",
doi = "10.1016/j.molcel.2020.12.026",
language = "English (US)",
volume = "81",
pages = "922--939.e9",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}