Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation

Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
Nature (Impact Factor: 41.46). 02/2012; 483(7390):484-8. DOI: 10.1038/nature10898
Source: PubMed


The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EGLN prolyl 4-hydroxylases that mark the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumours but can suppress tumour growth in some other contexts. IDH1 and IDH2, which catalyse the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumours and leukaemias. The resulting mutants have the neomorphic ability to convert 2-OG to the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). Here we show that (R)-2HG, but not (S)-2HG, stimulates EGLN activity, leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes. These findings define an enantiomer-specific mechanism by which the (R)-2HG that accumulates in IDH mutant brain tumours promotes transformation and provide a justification for exploring EGLN inhibition as a potential treatment strategy.

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Available from: Ryan E Looper, Apr 16, 2014
    • "Moreover, reports showed that mutations in the cytosolic isocitrate dehydrogenase (IDH1,2) may result in a decrease of aketoglutarate , thus stabilizing HIF-1a protein[Zhao et al., 2009]. More recent reports demonstrate that mutations in IDH1 or IDH2 result in the formation of abnormal metabolite (R)-2-hydroxyl- glutarate, which stimulates PHD activity, thus decreasing HIF-1a protein levels in gliomas[Koivunen et al., 2012]. However, clinical Fig. 1. "
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    ABSTRACT: HIF-1 activation has been well known as an adaptive strategy to hypoxia. Recently it became clear that hypoxia was often accompanied by insufficient supply of glucose or amino acids as a common result of poor circulation that frequently occurs in solid tumors and ischemic lesions, creating a mixed nutrient insufficiency. In response to nutrient insufficiency, stressed cells elicit survival strategies including activation of AMPK and HIF-1 to cope with the stress. Particularly, in solid tumors, HIF-1 promotes cell survival and migration, stimulates angiogenesis, and induces resistance to radiation and chemotherapy. Interestingly, radiation and some chemotherapeutics are reported to trigger the activation of AMPK. Here we discuss the recent advances that may potentially link the stress responsive mechanisms including AMPK activation, ATF4 activation and the enhancement of Hsp70/Hsp90 function to HIF-1 activation. Potential implication and application of the stress-facilitated HIF-1 activation in solid tumors and ischemic disorders will be discussed. A better understanding of HIF-1 activation in cells exposed to stresses is expected to facilitate the design of therapeutic approaches that specifically modulate cell survival strategy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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    • "Surprisingly, both (R)-2HG and (S)-2HG increase the lifespan of C. elegans (Figures 1B and 1C). Notably, (R)-2HG, (S)-2HG, and a-KG interact distinctly with the a-KG-dependent dioxygenases (Koivunen et al., 2012; Tarhonskaya et al., 2014). Therefore, the similar effect of a-KG and (R)-and (S)-2-HG on lifespan points to a common mechanism that is independent of dioxygenases or any enantiomer-specific 2-HG effects (da Silva et al., 2002; Latini et al., 2005; Wajne et al., 2002; Chan et al., 2015). "
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    ABSTRACT: We discovered recently that the central metabolite α-ketoglutarate (α-KG) extends the lifespan of C. elegans through inhibition of ATP synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various α-KG-mediated processes, similarly extends worm lifespan. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like α-KG, both (R)-2HG and (S)-2HG bind and inhibit ATP synthase and inhibit mTOR signaling. These effects are mirrored in IDH1 mutant cells, suggesting a growth-suppressive function of (R)-2HG. Consistently, inhibition of ATP synthase by 2-HG or α-KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, e.g., when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "nen et al . , 2012 ) . As mentioned above , 2HG inhibition of tumor suppressor genes of the TET and JmjC domain families causes aberrant histone demethylation and , finally , DNA methylated phenotype of IDH - mutated tumors ( Fig . 3 ; Xu et al . , 2011 ; Lu et al . , 2012 ) . However , 2HG does not inhibit all JmjC - domain histone demethylases ( Koivunen et al . , 2012 ) , and its exact role has yet to be resolved . Nevertheless , the oncometabolic effect of 2HG in IDH1 / 2 - mutated leukemia cells is sufficient to transform their ability to differentiate ( Losman et al . , 2013 ) . Also , inhibi - tion of mutant IDH1 R132H enzyme expression leads , in vitro , to a decrease in colony formation of IDH1"
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    ABSTRACT: Over the past few years, new biomarkers have allowed a deeper insight into gliomagenesis and facilitated the identification of possible targets for glioma therapy. Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations have been shown to be promising biomarkers for monitoring disease prognosis and predicting the response to treatment. This review summarizes recent findings in this field. Web of Science, Science Direct, and PubMed online databases were used to search for publications investigating the role of IDH in glioma. References were identified by searching for the keywords "IDH1 or IDH2 and glioma and diagnostic or predictive or prognostic" in papers published from January, 2008, to April, 2014. Only papers in English were reviewed. Publications available only as an abstract were not included. IDH1/2 mutations are tightly associated with grade II and III gliomas and secondary glioblastomas, with better prognosis and production of a recently described oncometabolite, 2-hydroxyglutarate (2HG). Although the contradictory positive effect of IDH mutation on prognosis and negative role of 2HG in tumor transformation remain unresolved, the future direction of personalized treatment strategies targeted to glioma development is likely to focus on IDH1/2 mutations. © 2014 Wiley Periodicals, Inc.
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