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R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling
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 promoti...
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Published in: | Cell 2018-01, Vol.172 (1-2), p.90-105.e23 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | 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.
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•R-2HG exhibits broad and variable anti-proliferation effects in leukemia and glioma•R-2HG increases global m6A RNA modification in the sensitive cells via targeting FTO•The R-2HG⊣FTO⊣m6A axis regulates MYC/CEBPA expression and downstream pathways•The FTO/MYC homeostasis controls the response/sensitivity of leukemia cells to R-2HG
While accumulation of the oncometabolite R-2-hydroxyglutarate (R-2HG) leads to cancer initiation, it also has anti-tumor effects in a subset of tumors by increasing global N6-methyladenosine (m6A) RNA modification. |
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ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2017.11.031 |