Searching across hundreds of databases
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.
Pubmed ID: 29249359 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsThis monoclonal targets FLAG
View all literature mentionsThis monoclonal targets CD33
View all literature mentionsThis polyclonal targets CEBP Alpha
View all literature mentionsThis monoclonal targets beta-actin
View all literature mentionsThis polyclonal targets goat anti-mouse IgG-HRP
View all literature mentionsThis polyclonal targets Rabbit IgG
View all literature mentionsThis monoclonal targets GAPDH
View all literature mentionsThis monoclonal targets c-Myc antibody [Y69]
View all literature mentionsThis polyclonal targets H3K36me3
View all literature mentionsThis polyclonal targets H3K9me3
View all literature mentionsThis monoclonal targets FTO antibody [EPR6895]
View all literature mentionsThis polyclonal targets 5-Hydroxymethylcytosine (5-hmC)
View all literature mentionsThe SciCrunch Infrastructure was developed as a cooperative data platform to be used by diverse communities in making data more FAIR.
scicrunch.org
