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

Rui Su1, Lei Dong1, Chenying Li2

  • 1Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.

Cell
|December 19, 2017
PubMed

Insights

R-2-hydroxyglutarate (R-2HG), a metabolite from mutant IDH1/2 enzymes, shows anti-leukemic effects by inhibiting FTO and decreasing MYC/CEBPA stability. This metabolite also demonstrates anti-tumor activity in glioma.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes elevate R-2-hydroxyglutarate (R-2HG), previously identified as an oncometabolite.
  • The role of R-2HG in cancer, particularly its potential therapeutic applications, requires further investigation.

Purpose of the Study:

  • To investigate the anti-leukemic and anti-tumor activities of R-2HG.
  • To elucidate the underlying molecular mechanisms of R-2HG's effects on cancer cells.

Main Methods:

  • In vitro and in vivo experiments using leukemia and glioma models.
  • Assessment of cell proliferation, viability, cell-cycle arrest, and apoptosis.
  • Analysis of FTO activity, m6A RNA modification levels, and MYC/CEBPA transcript stability.

Main Results:

  • R-2HG demonstrated broad anti-leukemic activity by inhibiting proliferation, inducing cell-cycle arrest, and promoting apoptosis.
  • R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, leading to increased m6A RNA modification.
  • This mechanism reduces MYC/CEBPA transcript stability, suppressing oncogenic pathways; similar effects were observed with mutant IDH1 and S-2HG.
  • High FTO levels sensitized cells to R-2HG, while MYC hyperactivation conferred resistance, which was reversible by MYC inhibition.
  • R-2HG also exhibited anti-tumor activity in glioma.

Conclusions:

  • R-2HG exhibits significant anti-tumor properties against leukemia and glioma by targeting the FTO/m6A/MYC/CEBPA signaling pathway.
  • While R-2HG contributes to cancer initiation in IDH1/2 mutant cancers, it also possesses therapeutic potential by inhibiting FTO-high cancer cell proliferation and survival.
  • The findings highlight R-2HG as a potential therapeutic agent and underscore the complex role of metabolites in cancer progression and treatment.
Keywords:
CEBPAFTOIDH mutationMYCN(6)-methyladenosine (m(6)A)R-2HGS-2HGgliomaleukemia

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