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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
Main Authors: Su, Rui, Dong, Lei, Li, Chenying, Nachtergaele, Sigrid, Wunderlich, Mark, Qing, Ying, Deng, Xiaolan, Wang, Yungui, Weng, Xiaocheng, Hu, Chao, Yu, Mengxia, Skibbe, Jennifer, Dai, Qing, Zou, Dongling, Wu, Tong, Yu, Kangkang, Weng, Hengyou, Huang, Huilin, Ferchen, Kyle, Qin, Xi, Zhang, Bin, Qi, Jun, Sasaki, Atsuo T., Plas, David R., Bradner, James E., Wei, Minjie, Marcucci, Guido, Jiang, Xi, Mulloy, James C., Jin, Jie, He, Chuan, Chen, Jianjun
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Language:English
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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. [Display omitted] •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.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2017.11.031