R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m 6 A/MYC/CEBPA Signaling

Cell. 2018 Jan 11;172(1-2):90-105.e23. doi: 10.1016/j.cell.2017.11.031. Epub 2017 Dec 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Brain Neoplasms / drug therapy*
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Line, Tumor
  • Glioma / drug therapy*
  • Glutarates / pharmacology*
  • Glutarates / therapeutic use
  • HEK293 Cells
  • Humans
  • Jurkat Cells
  • Leukemia / drug therapy*
  • Mice
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Processing, Post-Transcriptional
  • Signal Transduction / drug effects*


  • Antineoplastic Agents
  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, mouse
  • Glutarates
  • Proto-Oncogene Proteins c-myc
  • N6-methyladenosine (m6A)
  • alpha-hydroxyglutarate
  • FTO protein, mouse
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Adenosine