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

By P. Koivunen, Sungwoo Lee, Christopher G. Duncan, G. López, G. Lu, S. Ramkissoon, J. Losman, Päivi Joensuu, U. Bergmann, Stefan Gross and 7 more. Nature, 2012

736 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/132fc757dd3c06e21e7f3c92aaff980b091a54cf

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Citations in the corpus

Targeting Metabolism for Cancer Therapy (2017, background): “At these high concentrations, D-2HG can inhibit αKG-dependent dioxygenases, including enzymes involved in histone and DNA demethylation (Chowdhury et al., 2011; Janke et al., 2017; Koivunen et al., 2012; Xu et al., 2011).”
Influence of Metabolism on Epigenetics and Disease (2013, positive): “R-2HG, succinate, and fumarate are all capable of inhibiting multiple 2-oxoglutarate-dependent dioxygenases, including the JmjC histone demethylases and TET proteins, when present at sufficiently high concentrations (Figure 6B) (Cervera et al., 2009; Chowdhury et al., 2011; Figueroa et al., 2010; Ko”
Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “, 2015), and in turn, L2HG stabilizes HIF-1 protein levels by inhibiting PHD activity (Koivunen et al., 2012).”
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, neutral): “…by protein phosphatase 1 regulatory subunit 3C (PPP1R3C). verts α -ketoglutarate into D-2-hydroxyglutarate, which stimulates prolyl hydroxylase activity and results in decreased HIF-α protein levels (94), which contrasts with earlier reports of increased HIF-α levels in IDH-mutant cells (95).”
Mitochondria: In Sickness and in Health (2012, background): “Recent intriguing findings in gliomas indicated that IDH1 mutations contribute to gliomas via multiple mechanisms, including stabilizing hypoxia-inducible factor 1, as was previously found in other tumorigenic TCA defects, and by altering the methylation of CpG islands and histones, which causes wid”
Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “An additional report described an enantiomer-specific mechanism by which (R)-2HG, but not (S)-2HG, stimulated EGLN prolyl hydroxylase activity and consequent HIF-1α degradation (97).”
Lessons from the cancer genome. (2013, neutral): “, 2012) and prolyl-4-hydroxylases (EGLN1/2/3) that regulate hypoxia inducible factor (HIF), which is involved in certain cancers (Koivunen et al., 2012) (Figure 1).”
Fundamentals of cancer metabolism (2016, background): “L2HG and D2HG exhibit different effects on dioxygenase function (38), suggesting that the sensitivity of a particular tissue to the presence of either metabolite may depend on which dioxygenases are expressed.”