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

Jan 14, 2021

Contributor: Ying Qing,Lei Dong,Lei Gao,Chenying Li,Yangchan Li,Li Han,Emily Prince,Brandon Tan,Xiaolan Deng,Collin Wetzel,Chao Shen,Min Gao,Zhenhua Chen,Wei Li,Bin Zhang,Daniel Braas,Johanna Ten Hoeve,Gerardo Javier Sanchez,Huiying Chen,Lai N Chan,Chun-Wei Chen,David Ann,Lei Jiang,Markus Müschen,Guido Marcucci,David R Plas,Zejuan Li,Rui Su,Jianjun Chen

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

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)/N-methyladenosine (mA)/YTH N-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.
Copyright © 2020 Elsevier Inc. All rights reserved.

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About The Expert

Ying Qing

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.

Lei Dong

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.

Lei Gao

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.

Chenying Li

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.

Yangchan Li

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.

Li Han

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.

Emily Prince

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.

Brandon Tan

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.

Xiaolan Deng

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.

Collin Wetzel

Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.

Chao Shen

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.

Min Gao

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.

Zhenhua Chen

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.

Wei Li

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.

Bin Zhang

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.

Daniel Braas

UCLA Metabolomics Center, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Johanna Ten Hoeve

UCLA Metabolomics Center, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Gerardo Javier Sanchez

UCLA Metabolomics Center, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Huiying Chen

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.

Lai N Chan

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.

Chun-Wei Chen

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.

David Ann

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.

Lei Jiang

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.

Markus Müschen

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.

Guido Marcucci

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.

David R Plas

Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.

Zejuan Li

Department of Pathology and Genomic Medicine, Houston Methodist, Houston, TX 77030, USA.

Rui Su

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: rsu@coh.org.

Jianjun Chen

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.

References

PubMed