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
  • 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.