Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases
By W. Xu, Hui Yang, Ying Liu, Ying Yang, ping wang, Se-Hee Kim, Shinsuke Ito, Chen Yang, Pu Wang, Mengtao Xiao and 11 more. Cancer Cell, 2011
2,780 citations recorded by the source corpus.
SUMMARY IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.
View Paper: https://www.semanticscholar.org/paper/1eab592181cf264dbf0a09fd446d5913126fbc84
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Citations in the corpus
- Lessons from the cancer genome. (2013, unknown): “Studies then showed that 2HG appears to inhibit several a-KG-dependent enzymes (Xu et al., 2011), including Jumonji-C domain histone demethylases that affect gene expression (Lu et al.”
- Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. (2012, background): “…mutated IDH1 and IDH2 inhibits the activity of a-KG-dependent dioxygenases and, more importantly, produces 2-HG, which acts as an antagonist of a-KG to competitively inhibit the activity of a-KG-dependent dioxygenases, including both KDMs and TETs (Chowdhury et al. 2011; Xu et al. 2011).”
- R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling (2017, background): “Because IDH mutants block cell differentiation and promote tumor transformation, and inhibition of mutant IDH (IDHi) can reverse this effect, R-2HG (as the major metabolic product of IDH mutants) has been regarded as an oncometabolite (Figueroa et al., 2010; Lu et al., 2012; Rohle et al., 2013;Wang ”
- Glutaminolysis: A Hallmark of Cancer Metabolism. (2017, background): “Furthermore, activation of HIF1 can promote E3 ubiquitin–protein ligase SIAH2–dependent ubiquitination and subsequent degradation of oxoglutarate dehydrogenase 2 (OGDH2), a key enzyme for α-ketoglutarate conversion into succinate (58).”
- Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011, unknown): “In addition, genetic and functional studies suggest that neomorphic IDHmutations contribute tomyeloid transformation, at least in part, by inhibiting TET enzymatic function (Figueroa et al., 2010; Xu et al., 2011).”
- Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “Collective evidence stemming from several reports have highlighted that the pathophysiological role of 2HG is, at least in part, the competitive inhibition of various αKG-dependent dioxygenases, including TET2 DNA hydroxylases and JmjC histone demethylases (91, 92).”
- Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. (2012, background): “Methylation of K27 and K36 is also disrupted by elevated levels of the onco-metabolite 2-hydroxyglutarate (2-HG) resulting from gain-of-function mutations in IDH1 (Chowdhury et al., 2011; Xu et al., 2011), which was previously shown to be associated with a distinct Glioma-CpG-Island Methylator Pheno”