2. Academic Validation
  3. R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis

R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis

  • Mol Cell. 2021 Mar 4;81(5):922-939.e9. doi: 10.1016/j.molcel.2020.12.026.
Ying Qing 1,  Lei Dong 2,  Lei Gao 3,  Chenying Li 4,  Yangchan Li 5,  Li Han 6,  Emily Prince 2,  Brandon Tan 2,  Xiaolan Deng 2,  Collin Wetzel 7,  Chao Shen 2,  Min Gao 8,  Zhenhua Chen 2,  Wei Li 2,  Bin Zhang 9,  Daniel Braas 10,  Johanna Ten Hoeve 10,  Gerardo Javier Sanchez 10,  Huiying Chen 2,  Lai N Chan 11,  Chun-Wei Chen 12,  David Ann 13,  Lei Jiang 14,  Markus Müschen 15,  Guido Marcucci 9,  David R Plas 7,  Zejuan Li 16,  Rui Su 17,  Jianjun Chen 18
Affiliations

Affiliations

  • 1 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
  • 2 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • 3 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pathology and Genomic Medicine, Houston Methodist, Houston, TX 77030, USA.
  • 4 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 31003, China.
  • 5 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • 6 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
  • 7 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
  • 8 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineer (Tianjin), Tianjin University, Tianjin 300072, China.
  • 9 Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA; Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.
  • 10 UCLA Metabolomics Center, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 11 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Internal Medicine (Hematology) and Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06511, USA.
  • 12 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA.
  • 13 Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA.
  • 14 Molecular and Cellular Endocrinology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA.
  • 15 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA; Department of Internal Medicine (Hematology) and Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06511, USA.
  • 16 Department of Pathology and Genomic Medicine, Houston Methodist, Houston, TX 77030, USA.
  • 17 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: rsu@coh.org.
  • 18 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA; Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA. Electronic address: jianchen@coh.org.
PMID: 33434505 DOI: 10.1016/j.molcel.2020.12.026
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.

Keywords

FTO; LDHB; N(6)-methyladenosine (m(6)A) modification; PFKP; R-2HG; RNA stability; YTHDF2; cancer metabolism; glycolysis; leukemia.

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