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

By R. Su, Lei Dong, Chenying Li, S. Nachtergaele, M. Wunderlich, Y. Qing, Xiaolan Deng, Yungui Wang, X. Weng, Chao Hu and 22 more. Cell, 2017

977 citations recorded by the source corpus.

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 promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits 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.

Subfields: Cardiology and Cardiovascular Medicine, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a88d785f21c442e9b128863ab6345dbdd38a8f46

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In Molecular Biology

1. Chuan He
2. P. He
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4. Jiangbo W
5. Jianjun Chen
6. Huilin Huang
7. Hengyou Weng
8. Bryan T. Harada

Citations in the corpus

• Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia (2019, background): “any further significant fold changes of these hyper peaks in MONOMAC6 AML cells (Figures 6E and 6F), which is consistent with reported observations in AML cells with FTO KD or R-2HG treatment (Su et al., 2018).”
• Gene2vec: gene subsequence embedding for prediction of mammalian N6-methyladenosine sites from mRNA (2018, background): “2017), andm(6)Amodification was also shown to exert anti-leukemic activity in recent studies (Li et al. 2017b; Su et al. 2018).”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “In these cells up to ~40% of all mRNA m6A are subjected to demethylation by FTO (Li et al., 2017; Su et al., 2018; Wei et al., 2018).”
• METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification (2017, background): “Interestingly, while METTL14 promotes stability ofMYCmRNA through affecting m(6)A abundance mainly on the 30-terminal exon, we very recently show that FTO also promotes stability of MYC mRNA through inhibition of YTHDF2mediated RNA decay attributed to decreased m(6)A abundance on the 50-terminal and”
• Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “20 In zebrafish, Ythdf2 deletion in embryos decelerates the decay of m6A-modified maternal mRNAs and impedes zygotic genome activation.23 Our recent study revealed that YTHDF2-mediated decay of transcripts of the arterial endothelial genes notch1a and rhoca contributes to the emergence of haematopoi”
• m6A RNA methylation: from mechanisms to therapeutic potential (2021, positive): “FTO is upregulated in a subset of AML and plays oncogenic roles (Li et al , 2017c; Su et al , 2018), including the gain of resistance to tyrosine kinase inhibitor therapy (Yan et al , 2018).”
• RNA modifications modulate gene expression during development (2018, positive): “Inhibition of FTO reduces AML cell proliferation and viability in these cell types ( 59, 60 ).”
• m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer (2018, positive): “Other types of tumors could exploit aberrant RNA methylation to gain survival and growth advantages via AKT activation in addition to other proposed mechanisms 24–35 .”
• The potential role of RNA N6-methyladenosine in Cancer progression (2020, background): “In addition, some researchers have focused on targeted cancer therapies related to m6A, such as treatment with R-2HG to increase m6A mRNA modification in R-2HG-sensitive leukemia cells by inhibiting FTO activity, thus generating antileukemia effects [151].”
• Targeting FTO suppresses cancer stem cell maintenance and immune evasion (2020, positive): “Western blot assay was performed as described previously (Su et al., 2018).”
• Functions of N6-methyladenosine and its role in cancer (2019, background): “As a metabolite by mutant IDH1/2 enzymes, R-2hydroxyglutarate (R-2HG) elevates m6A level and enhances the YTHDF2-mediated-degradation of MYC, ASB2, and RARA [160].”