期刊
CELL
卷 172, 期 1-2, 页码 90-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2017.11.031
关键词
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资金
- NIH [CA214965, CA211614, CA178454, CA182528, RM1 HG008935, GM071440, R50 CA211404, R01NS089815, R21NS100077]
- Foundation of Innovation Team for Basic and Clinical Research of Zhejiang Province [2011R50015]
- Academic and Research Committee of Cincinnati Children's Hospital Medical Center
- Damon Runyon Cancer Research Foundation [DRG-2215-15]
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 N-6-methyladenosine (m(6)A) 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/m(6)A/MYC/CEBPA signaling.
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