2. Academic Validation
  3. R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling

R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling

  • Cell. 2018 Jan 11;172(1-2):90-105.e23. doi: 10.1016/j.cell.2017.11.031.
Rui Su 1,  Lei Dong 1,  Chenying Li 2,  Sigrid Nachtergaele 3,  Mark Wunderlich 4,  Ying Qing 1,  Xiaolan Deng 5,  Yungui Wang 2,  Xiaocheng Weng 6,  Chao Hu 2,  Mengxia Yu 7,  Jennifer Skibbe 1,  Qing Dai 3,  Dongling Zou 8,  Tong Wu 3,  Kangkang Yu 3,  Hengyou Weng 1,  Huilin Huang 1,  Kyle Ferchen 1,  Xi Qin 1,  Bin Zhang 9,  Jun Qi 10,  Atsuo T Sasaki 11,  David R Plas 1,  James E Bradner 10,  Minjie Wei 12,  Guido Marcucci 9,  Xi Jiang 1,  James C Mulloy 4,  Jie Jin 13,  Chuan He 14,  Jianjun Chen 15
Affiliations

Affiliations

  • 1 Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
  • 2 Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
  • 3 Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
  • 4 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 5 Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
  • 6 Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, Wuhan University, Hubei, Wuhan 430072, China.
  • 7 Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
  • 8 Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Depart of Gynecologic Oncology, Chongqing Cancer Institute and Hospital and Cancer Center, Chongqing 400030, China.
  • 9 Gehr Family Center for Leukemia Research, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA.
  • 10 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 11 Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
  • 12 School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
  • 13 Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China. Electronic address: [email protected].
  • 14 Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
  • 15 Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Gehr Family Center for Leukemia Research, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA. Electronic address: [email protected].
PMID: 29249359 DOI: 10.1016/j.cell.2017.11.031
Abstract

R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and Apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N6-methyladenosine (m6A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to Cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high Cancer cells via targeting FTO/m6A/MYC/CEBPA signaling.

Keywords

CEBPA; FTO; IDH mutation; MYC; N(6)-methyladenosine (m(6)A); R-2HG; S-2HG; glioma; leukemia.

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