The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index; none of the 22 sources its claims cite is checked for support yet.
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases
Open accessAbstract
Mutations in isocitrate dehydrogenases (IDHs) have a gain-of-function effect leading to R(-)-2-hydroxyglutarate (R-2HG) accumulation. By using biochemical, structural and cellular assays, we show that either or both R- and S-2HG inhibit 2-oxoglutarate (2OG)-dependent oxygenases with varying potencies. Half-maximal inhibitory concentration (IC(50)) values for the R-form of 2HG varied from approximately 25 μM for the histone N(ɛ)-lysine demethylase JMJD2A to more than 5 mM for the hypoxia-inducible factor (HIF) prolyl hydroxylase. The results indicate that candidate oncogenic pathways in IDH-associated malignancy should include those that are regulated by other 2OG oxygenases than HIF hydroxylases, in particular those involving the regulation of histone methylation.
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“Structures of FIH and JMJD2A with R-or S-2HG show that both can bind to the active site iron, or surrogate nickel, in a bidentate manner (Fig 2).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
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“Of the two 2HG enantiomers, the S-form was the more-potent inhibitor.”
- Also stated in: § DISCUSSION · plain
“For most of the 2OG oxygenases tested in vitro, S-2HG was more potent than R-2HG (Table 1).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
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“Half-maximal inhibitory concentration (IC 50 ) values for the R-form of 2HG varied from approximately 25 lM for the histone N e -lysine demethylase JMJD2A to more than 5 mM for the hypoxia-inducible factor (HIF) prolyl hydroxylase.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > Abstract
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“Consistent with in vitro data, we observed a clear reduction in HIF1a Asn-hydroxylation, that was greater with S-than R-2HG.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > R-/S-2HG.
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“We found this is the case (Fig 3F).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > R-/S-2HG.
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“Our results therefore support the candidacy of one or more of these enzymes as targets for pathologically relevant 2HG”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > DISCUSSION
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“As production of 2HG by IDH mutations is stereospecific (Dang et al, 2009;Ward et al, 2010), the specificity of inhibition by the 2HG enantiomers is relevant to their potential as mediators of oncogenic pathways.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > DISCUSSION
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“Although the inhibition potencies are generally weak, we observe broad concordance between the in vitro and in vivo results (Table 1; Figs 1 and 3).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > DISCUSSION
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“The weak inhibition of the HIF hydroxylases suggests that the pathological effects of 2HG are probably not, at least predominantly, mediated by direct inhibition of HIF hydroxylases.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
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“However, they show that elevated 2HG levels might regulate gene expression by inhibition of 2OG-dependent chromatin-modifying enzymes, including the JmjC histone demethylases.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > Additional information
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In the paper
“By contrast, inhibition of PHD2 and BBOX1 by R-2HG was weak, with IC 50 values of approximately 7 and 13 mM, respectively, consistent with previous work with the PHDs (Mole et al, 2003).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
What the sources say
- Not checked yetcites Mole et al, 2003 source
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“The other oxygen of the 2HG C1-carboxylate is positioned to hydrogen bond to Nd2 of N205 FIH (Fig 2A,B) or to Og of S288 JMJD2A (Fig 2D,E); the 2HG C5-carboxylate is positioned to hydrogen bond to K214 FIH Nz, Y145 FIH OH and T196 FIH Og1 (Fig 2A,B) and to K206 JMJD2A Nz and Y132 JMJD2A OH (Fig 2D,E), as observed for the 2HG C5-carboxylate.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
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“Neither dose of R-2HG induced HIF1a.Modest induction was observed with S-2HG (Fig 3E).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > R-/S-2HG.
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“Nevertheless, PHD2 is poorly inhibited in vitro by R-2HG (Fig 1; Table 1), and we were unable to demonstrate inhibition of the PHDs sufficient to substantially upregulate HIF in cells (Fig 3C-E).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > Additional information
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“We investigated whether R-or S-2HG is oxidized to 2OG by PHD2 and FIH; in our standard conditions, we did not find conversion of 2HG to 2OG by NMR analysis (data not shown).Neither R-nor S-2HG was a cosubstrate for PHD2 (supplementary Fig S1 online).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
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In the paper
“At high concentrations (8 Â 5 mM or 10-mM additions at 30-min intervals), both enantiomers inhibited JMJD2A in a dose-dependent manner (Fig 3B); consistent with the in vitro data, the extent of inhibition was similar for S”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The cell-penetrating ester forms of R-2HG and S-2HG are hydrolysed inside cells to deliver sufficient 2HG to inhibit JMJD2A.
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In the paper
“Similarly to 2OG and NOG (Elkins et al, 2003;Ng et al, 2007), both R-and S-2HG coordinate the metal with the 2-hydroxyl group trans to D201 FIH /E190 JMJD2A and one oxygen of the the C1-carboxylate trans to H199 FIH /H188 JMJD2A (Fig 2A,B,D,E).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
What the sources say
- Not checked yetcites Elkins et al, 2003 source
- Not checked yetcites Ng et al, 2007
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“Only with the histone N e -methyl lysine demethylases JMJD2A/C were both enantiomers of similar potency, and of the enzymes tested, JMJD2A was the only one for which R-2HG showed similar potency to NOG, a 'generic' 2OG oxygenase inhibitor.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > DISCUSSION
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“In contrast to these results and consistent with the in vitro data, we observed no R-2HG and only minimal S-2HG inhibition of Pro-hydroxylation, when using the same doses at which JMJD2A was inhibited (exposure to higher 2HG doses was toxic).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > R-/S-2HG.
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In the paper
“By using biochemical, structural and cellular assays, we show that either or both R-and S-2HG inhibit 2-oxoglutarate (2OG)-dependent oxygenases with varying potencies.”
- Also stated in: § RESULTS · plain
“these results show that both R-and S-2HG inhibit the 2OG oxygenases, but with different potencies.”
- Also stated in: § DISCUSSION · hedged
“Overall, our results demonstrate that R-and S-2HG have the potential to inhibit a range of human 2OG oxygenases”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > Abstract
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In the paper
“For R-2HG, the most significant inhibition was of JMJD2A, for which the IC 50 (24 mM) was similar to that observed for NOG (17 mM).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
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In the paper
“The lack of a substantial increase in IC 50 values at higher (10-fold) iron concentrations (for JMJD2A and BBOX-1), and different values for the two enantiomers imply that the mode of inhibition is not predominantly iron sequestration (Table 1).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
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In the paper
“These results suggest that 2HG-and in particular the R-enantiomer produced by IDH1 mutants (Dang et al, 2009)-is probably an ineffective inhibitor of HIF Pro-hydroxylation, and predict that it would be relatively ineffective in inducing HIF1a.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > R-/S-2HG.
What the sources say
- Not checked yetcites Dang et al, 2009 source
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In the paper
“Overall, the crystallographic analyses indicte that, similarly to succinate and fumarate (Fig 2C,F; Hewitson et al, 2007), both R-and S-2HG have the potential to bind to the active site Fe(II) and compete with 2OG for binding.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > RESULTS
What the sources say
- Not checked yetcites Hewitson et al, 2007 source
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In the paper
“The HIF hydroxylases are Fe(II)-and 2OG-dependent oxygenases that produce succinate and CO 2 as coproducts; the HIF prolyl hydroxylases (PHD/EGLN enzymes) signal for HIF degradation, whereas factor inhibiting-HIF (FIH) is an asparaginyl hydroxylase that reduces HIF activity (Kaelin & Ratcliffe, 2008).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > INTRODUCTION
What the sources say
- Not checked yetcites Kaelin & Ratcliffe, 2008 source
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In the paper
“Inhibition of Asn-hydroxylation in the C-terminal transactivation domain of HIFa polypeptides might be predicted to enhance transcriptional activity through the recruitment of p300/ CBP coactivators to the C-terminal activation domain (Kaelin & Ratcliffe, 2008).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > Additional information
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- Not checked yetcites Kaelin & Ratcliffe, 2008 source
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In the paper
“All assays were performed in triplicate and are shown as averages with s.e.m.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > DISCUSSION
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In the paper
“HIF is stabilized in IDH-associated gliomas; this has been proposed to be a consequence of intracellular depletion of 2OG following IDH loss of function (Zhao et al, 2009).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > Additional information
What the sources say
- Not checked yetcites Zhao et al, 2009 source
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In the paper
“As HIF transcriptional target genes are differently dependent on the activity of this domain, such an action might affect hypoxia pathways.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > Additional information
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In the paper
“Data were normalized by setting DMSO-treated JMJD2A-transfected cells to 100% activity and a catalytically inactive JMJD2A H188A mutant to 0% activity.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > Additional information
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- Rests on an assumption: The JMJD2A H188A mutant is catalytically inactive and therefore provides a valid 0% activity baseline.
In the paper
“Other 2OG oxygenases are associated with cancer, including the JmjC histone demethylases (Varier & Timmers, 2010).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > INTRODUCTION
What the sources say
- Not checked yetcites Varier & Timmers, 2010
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In the paper
“The results indicate that 2HG is a relatively poor inhibitor of the HIF hydroxylases in comparison to the 2OG-dependent histone lysyl demethylases, suggesting that candidate oncogenic pathways involving 2HG elevation might involve chromatin modifications.”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > INTRODUCTION
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In the paper
“The IDH mutations occur at substrate-binding arginine residues (Arg 132 in IDH1; Arg 140 and Arg 172 in IDH2) and inactivate IDH for conversion of isocitrate to 2-oxoglutarate (2OG; Zhao et al, 2009).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > INTRODUCTION
What the sources say
- Not checked yetcites Zhao et al, 2009 source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper relies on this without support.
The cell-penetrating ester forms of R-2HG and S-2HG are hydrolysed inside cells to deliver sufficient 2HG to inhibit JMJD2A.
“A cell-penetrating ester form of R-/S-2HG ABH2, AlkB homologue 2; BBOX1, g-butyrobetaine hydroxylase 1; FIH, factor inhibiting-hypoxia-inducible factor; HIF, hypoxia-inducible factor; NOG, N-oxalylglycine; 2OG, 2-oxoglutarate; PHD2, prolyl hydroxylase 2; R-2HG, R-enantiomer of 2-hydroxyglutarate; IC 50 , half-maximal inhibitory concentration.”
“At high concentrations (8 Â 5 mM or 10-mM additions at 30-min intervals), both enantiomers inhibited JMJD2A in a dose-dependent manner (Fig 3B); consistent with the in vitro data, the extent of inhibition was similar for S”
The paper relies on this without support.
IC50 values obtained under different assay conditions for different enzymes can be compared to rank their relative potency.
“Although care must be taken in comparing IC 50 values determined with different assay conditions for the various oxygenases, these results show that both R-and S-2HG inhibit the 2OG oxygenases, but with different potencies.”
The paper relies on this without support.
The JMJD2A H188A mutant is catalytically inactive and therefore provides a valid 0% activity baseline.
“Data were normalized by setting DMSO-treated JMJD2A-transfected cells to 100% activity and a catalytically inactive JMJD2A H188A mutant to 0% activity.”
Claims other papers make about this one
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In the citing paper
“Though it is found at low levels in normal cells, D-2HG can accumulate to millimolar levels in cancer cells expressing mutant IDH. 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).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Chowdhury et al., 2011
In the citing paper
“Intracellular 2-oxoglutarate levels are estimated to be in the low millimolar range, well above the 2-oxoglutarate Km values of the JmjC histone demethylases and TET proteins determined to date (Chowdhury et al., 2011; Pritchard, 1995).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Chowdhury et al., 2011
In the citing paper
“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; Koivunen et al., 2012; Lu et al., 2012; Smith et al., 2007; Turcan et al., 2012; Xiao et al., 2012; Xu”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Chowdhury et al., 2011
In the citing paper
“The weight of the evidence now suggests that regulation of HIF-1 stability through decreased PHD2 activity is not the primary effect of IDH mutations (Chowdhury et al., 2011; Dang et al., 2009; Jin et al., 2011; Mardis et al., 2009; Metellus et al., 2011; Williams et al., 2011).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Chowdhury et al., 2011
In the citing paper
“Furthermore, TH17 cell differentiation could be initiated by exogenous addition of D-2-HG to naïve CD4+ T cells or by genetic silencing of TET1 and TET2, established targets of 2-HG143-145.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [144]
Citations
Cites
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251 · cited 3×
“…HIF hydroxylases are Fe(II)- and 2OG-dependent oxygenases that produce succinate and CO2 as coproducts; the HIF prolyl hydroxylases (PHD/EGLN enzymes) signal for HIF degradation, whereas factor inhibiting-HIF (FIH) is an asparaginyl hydroxylase that reduces HIF activity (Kaelin & Ratcliffe, 2008).”
BackgroundInfluentialSelf-citationSuccinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108 · cited 1×
“The HIF hydroxylases function as negative regulators of HIFmediated transcription (Isaacs et al, 2005; Selak et al, 2005; Hewitson et al, 2007); thus, increased levels of succinate and fumarate are thought to promote tumour growth by inhibition of the HIF hydroxylases.”
BackgroundWard, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.020 · Cited by 2,020 · cited 3×
“However, they also cause a gain of function comprising catalysis of 2OG to the R-enantiomer of 2-hydroxyglutarate (R-2HG; Dang et al, 2009; Gross et al, 2010; Ward et al, 2010).”
BackgroundInfluentialDefining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
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Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes
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Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
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Self-citationSomatic mutations of the histone H3K27 demethylase gene UTX in human cancer
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Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
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“Although one initial report implicated a broad array of enzymes that were affected by 2HG (Xu et al., 2011), a later report suggested greater specificity of 2HG for some specific Jumonji C domain histone demethylases (Chowdhury et al., 2011).”
BackgroundFundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
Wallace, D. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3365 · Cited by 2,404
IDH mutation impairs histone demethylation and results in a block to cell differentiation
Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C. R., Khanin, R., Figueroa, M. E., Melnick, A., et al. (2012) · Nature · doi:10.1038/nature10860 · Cited by 1,985
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“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 Phenotype (G-CIMP) (Nous…”
BackgroundTargeting cancer metabolism: a therapeutic window opens
Heiden, M. G. V. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3504 · Cited by 1,443
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“We and others recently demonstrated that ectopic expression of tumor-derived 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…”
An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells
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R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling
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“R-2HG has also been shown to competitively inhibit the functions of DNA and histone demethylases, such as TET2, JMJD, and KDM, leading to hypermethylated DNA and histones (Chowdhury et al., 2011; Sasaki et al., 2012).”
BackgroundTargeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971
“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).”
BackgroundDynamic Readers for 5-(Hydroxy)Methylcytosine and Its Oxidized Derivatives
Spruijt, C. G., Gnerlich, F., Smits, A. H., Pfaffeneder, T., Jansen, P. W. T. C., Bauer, C., Münzel, M., Wagner, M., Müller, M., Khan, F., et al. (2013) · Cell · doi:10.1016/j.cell.2013.02.004 · Cited by 973
“It has been shown that oncometabolites such as 2-hydroxyglutarate can competitively inhibit the activity of 2-oxo-glutarate-dependent enzymes, such as the Tet proteins (Chowdhury et al., 2011; Xu et al., 2011).”
Links between metabolism and cancerPreprint
Dang, C. V. (2012) · Genes & Development · doi:10.1101/gad.189365.112 · Cited by 1,021
How cancer metabolism is tuned for proliferation and vulnerable to disruption
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Influence of Metabolism on Epigenetics and Disease
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“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; Koivunen et al., 2012…”
Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation
Wang, F., Travins, J., DeLaBarre, B., Penard-Lacronique, V., Schalm, S., Hansen, E., Straley, K., Kernytsky, A., Liu, W., Gliser, C., et al. (2013) · Science · doi:10.1126/science.1234769 · Cited by 804
Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma
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“…Surgery and Medicine, Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065, USA 13These authors contributed equally to this work *Correspondence: gmurphy@rics.bwh.harvard.edu (G.F.M.), yujiang_shi@hms.harvard.edu (Y.G.S.) http://dx.doi.org/10.1016/j.cell.2012.07.033”
BackgroundInfluentialMetabolic reprogramming and epigenetic modifications on the path to cancer
Sun, L., Zhang, H., & Gao, P. (2021) · Protein & Cell · doi:10.1007/s13238-021-00846-7 · Cited by 818
“There are two enantiomeric forms of 2HG, D-(or R-) and L-(or S-) type 2-HG, all of which are α-KG inhibitors that inhibit α-KG-dependent histone lysine demethylases, such as FIH (factor inhibiting HIF), PHD2 (prolyl hydroxylase domain-containing protein, also known as HIF prolyl-hydroxylase 2), and JMJDs (Chowdhury et…”
BackgroundTransformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation
Koivunen, P., Lee, S., Duncan, C. G., Lopez, G., Lu, G., Ramkissoon, S., Losman, J. A., Joensuu, P., Bergmann, U., Gross, S., et al. (2012) · Nature · doi:10.1038/nature10898 · Cited by 727
Metabolic Regulation of Epigenetics
Lu, C., & Thompson, C. B. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.06.001 · Cited by 699
“Biochemical studies suggest that 2HG can inhibit a number of aKG-dependent enzymes with varying potencies, therefore the challenge is to identify key enzymes that mediate 2HG’s oncogenic effect (Chowdhury et al., 2011; Xu et al., 2011b).”
BackgroundInfluential( R )-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible
Losman, J.-A., Looper, R. E., Koivunen, P., Lee, S., Schneider, R. K., McMahon, C., Cowley, G. S., Root, D. E., Ebert, B. L., & Kaelin, W. G. (2013) · Science · doi:10.1126/science.1231677 · Cited by 703
The role of mutations in epigenetic regulators in myeloid malignancies
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“In addition to inhibiting TET2 dioxygenase activity, 2-HG also inhibits other a-KG-dependent proteins, including members of the Jumonji-C (JMJC) domain histone demethylase family (61).”
BackgroundIDH mutation in glioma: molecular mechanisms and potential therapeutic targets
Han, S., Liu, Y., Cai, S. J., Qian, M., Ding, J., Larion, M., Gilbert, M. R., & Yang, C. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0814-x · Cited by 701
Metabolomics in cancer research and emerging applications in clinical oncology
Schmidt, D. R., Patel, R., Kirsch, D. G., Lewis, C. A., Heiden, M. G. V., & Locasale, J. W. (2021) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21670 · Cited by 675
What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer
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“2), and it has been proposed that (R)-2HG transforms cells by competitively inhibiting 2OG-dependent enzymes that function as tumor suppressors (Chowdhury et al. 2011; Xu et al. 2011; Koivunen et al. 2012; Lu et al. 2012).”
BackgroundEmerging insights into the molecular and cellular basis of glioblastomaPreprint
Dunn, G. P., Rinne, M. L., Wykosky, J., Genovese, G., Quayle, S. N., Dunn, I. F., Agarwalla, P. K., Chheda, M. G., Campos, B., Wang, A., et al. (2012) · Genes & Development · doi:10.1101/gad.187922.112 · Cited by 573
“The inhibition of histone demethylases in IDH1 mutant cells may also impair differentiation (Chowdhury et al. 2011; Xu et al. 2011; Lu et al. 2012).”
BackgroundThe emerging role and targetability of the TCA cycle in cancer metabolism
Anderson, N. M., Mucka, P., Kern, J. G., & Feng, H. (2017) · Protein & Cell · doi:10.1007/s13238-017-0451-1 · Cited by 586
Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge
Sturm, D., Bender, S., Jones, D. T. W., Lichter, P., Grill, J., Becher, O., Hawkins, C., Majewski, J., Jones, C., Costello, J. F., et al. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3655 · Cited by 555
The impact of cellular metabolism on chromatin dynamics and epigenetics
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Hypoxia Induces Production of L-2-Hydroxyglutarate
Intlekofer, A. M., Dematteo, R. G., Venneti, S., Finley, L. W. S., Lu, C., Judkins, A. R., Rustenburg, A. S., Grinaway, P. B., Chodera, J. D., Cross, J. R., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.023 · Cited by 513
“Previous reports demonstrated that L-2HG can stabilize HIF1a in normoxia viaL-2HG-mediated inhibitionof theEGLNfamilyofa-KG-dependent prolyl hydroxylases that mark HIF1a for proteasomal degradation (Chowdhury et al., 2011; Koivunen et al., 2012).”
BackgroundInfluentialIDH mutations in cancer and progress toward development of targeted therapeutics
Dang, L., Yen, K., & Attar, E. C. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw013 · Cited by 509
“High levels of 2-HG have been shown to inhibit αKG-dependent dioxygenases including histone and DNA demethylases, proteins that regulate cellular epigenetic status [23–25] (Figure 1).”
BackgroundIDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics
Sasaki, M., Knobbe, C. B., Munger, J. C., Lind, E. F., Brenner, D., Brüstle, A., Harris, I. S., Holmes, R., Wakeham, A., Haight, J., et al. (2012) · Nature · doi:10.1038/nature11323 · Cited by 513
Hypoxia-Modified Cancer Cell Metabolism
Tameemi, W. A., Dale, T. P., Al-Jumaily, R. M. K., & Forsyth, N. R. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00004 · Cited by 524
“, fumarate hydratase (FH), the subunits of succinate dehydrogenase (SDH), and isocitrate dehydrogenase (IDH1 and IDH2)] can give rise to a condition termed pseudo-hypoxia by formation of a reduced variety of 2-oxoglutarate, (R)-2-hydroxyglutarate, as an oncometabolite, involving activation of HIF-1, irrespective of a…”
Background2-Oxoglutarate-Dependent Oxygenases
Islam, M. S., Leissing, T. M., Chowdhury, R., Hopkinson, R. J., & Schofield, C. J. (2018) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044724 · Cited by 472
Self-citationAG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
Yen, K., Travins, J., Wang, F., David, M. D., Artin, E., Straley, K., Padyana, A., Gross, S., DeLaBarre, B., Tobin, E., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1034 · Cited by 471
Mitochondria as Signaling Organelles Control Mammalian Stem Cell Fate
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“Besides, being structurally similar to α-KG, succinate, fumarate, and 2-hydroxyglutarate (both D- and L- isoforms) can competitively inhibit TETs and KDMs and thereby regulate gene expression (Chowdhury et al., 2011; Schvartzman et al., 2018; Xu et al., 2011).”
BackgroundIDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives
Yang, H., Ye, D., Guan, K., & Xiong, Y. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1773 · Cited by 477
“This hypothesis was experimentally shown for multiple a-KG– dependent dioxygenases, in particular histone lysine demethylases (KDMs) and the TET family of DNA hydroxylases both in vitro and in vivo (42, 69).”
BackgroundOncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities
Cairns, R. A., & Mak, T. W. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0083 · Cited by 452
Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion
Tateishi, K., Wakimoto, H., Iafrate, A. J., Tanaka, S., Loebel, F., Lelic, N., Wiederschain, D., Bedel, O., Deng, G., Zhang, B., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.11.006 · Cited by 433
“…and 5-methylcytosine hydroxylases, resulting in altered HIF activity, widespread chromatin alterations and a stem-like cell differentiation block (Figueroa et al., 2010; Koivunen et al., 2012; Losman et al., 2013; Lu et al., 2012; Saha et al., 2014; Chowdhury et al., 2011; Xu et al., 2011).”
KDM4/JMJD2 Histone Demethylases: Epigenetic Regulators in Cancer Cells
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“1C), which is an inhibitor of KDM4 proteins (72).”
BackgroundOxygen availability and metabolic adaptations
Nakazawa, M. S., Keith, B., & Simon, M. C. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.84 · Cited by 446
S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate
Tyrakis, P. A., Palazon, A., Macias, D., Lee, K. L., Phan, A. T., Veliça, P., You, J., Chia, G. S., Sim, J., Doedens, A., et al. (2016) · Nature · doi:10.1038/nature20165 · Cited by 433
Altered metabolite levels in cancer: implications for tumour biology and cancer therapy
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Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer
Mohammad, H. P., Barbash, O., & Creasy, C. L. (2019) · Nature Medicine · doi:10.1038/s41591-019-0376-8 · Cited by 427
The language of chromatin modification in human cancers
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Coupling Krebs cycle metabolites to signalling in immunity and cancer
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The implications of IDH mutations for cancer development and therapy
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Cancer metabolism: current perspectives and future directions
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“However a recent study indicated that an upregulation of HIF by 2HG is unlikely to be the major factor in IDH mutation-associated oncogenesis.(55) Even though IDH1 and IDH2 were not the first metabolic enzymes to be involved in oncogenesis, they were the first to link metabolite production to oncogenesis(56) with majo…”
BackgroundMetabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis
Daye, D., & Wellen, K. E. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.02.002 · Cited by 387
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“2Hydroxyglutarate accumulation has been shown to promote tumorigenesis by competitively inhibiting αketoglutarate– dependent dioxygenases, which include histone lysine demethylases and DNA demethylases.(49,50) This results in histone and DNA hypermethylation with a CpG island methylator phenotype pattern, leading to a…”
BackgroundUnderstanding metabolic regulation and its influence on cell physiology
Metallo, C. M., & Vander Heiden, M. G. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.018 · Cited by 367
Isocitrate dehydrogenase mutations in myeloid malignancies
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Metabolic signaling in T cells
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Biological Role and Therapeutic Potential of IDH Mutations in Cancer
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Metabolic Regulation of Histone Post-Translational Modifications
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A machine learning approach to integrate big data for precision medicine in acute myeloid leukemia
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“In addition, histone demethylases are competitively blocked by 2-HG 31 .”
BackgroundIvosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma
Mellinghoff, I. K., Ellingson, B. M., Touat, M., Maher, E. A., de la Fuente, M. I., Holdhoff, M., Cote, G. M., Burris, H. A., Jankú, F., Young, R. J., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.19.03327 · Cited by 330
Metabolic signatures of cancer cells and stem cells
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“…function of α -KG- dependent dioxygenases, such as the JmjC domain-containing histone demethylases (JmjC-KDMs) , which cause histone demethylation 5,14,15 , and the ten-eleven translocation (TET) family of DNA hydroxylases, which cause DNA demethylation 5,16 and are considered a major mechanism in…”
The mitochondrial respiratory chain is essential for haematopoietic stem cell function
Ansó, E., Weinberg, S. E., Diebold, L. P., Thompson, B. J., Malinge, S., Schumacker, P. T., Liu, X., Zhang, Y., Shao, Z., Steadman, M., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3529 · Cited by 327
“L (S)-2-HG is a more potent inhibitor of α -KG-dependent dioxygenases than D(R)-2-HG or succinate 34 .”
Dysregulated metabolism contributes to oncogenesis
Hirschey, M. D., DeBerardinis, R. J., Diehl, A. M., Drew, J. E., Frezza, C., Green, M. F., Jones, L. W., Ko, Y. H., Le, A., Lea, M. A., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.10.002 · Cited by 316
“(R)-2HG is thought to act by competitively inhibiting certain enzymes that require -KG as a cofactor, including Jumonji-C domain histone demethylases (JHDMs) and TET proteins, which are implicated in DNA demethylation [211,212].”
WT1 Recruits TET2 to Regulate Its Target Gene Expression and Suppress Leukemia Cell Proliferation
Wang, Y., Xiao, M., Chen, X., Chen, L., Xu, Y., Lv, L., Wang, P., Yang, H., Ma, S., Lin, H., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2014.12.023 · Cited by 320
“…catalytically inactivated by D-2-hydroxyglutarate (D-2-HG), an oncometabolite produced by mutated isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) (Chowdhury et al., 2011; Xu et al., 2011), which occurs in about 20% of AMLs in a mutually exclusive manner with TET2 mutations (Figueroa et al.,…”
Role of mitochondrial dysfunction in cancer progression
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“The increased 2-hydroxyglutarate levels were shown to be associated with DNA hypermethylation and a broad epigenetic change, which results in epigenetic alterations of gene expression.(113,117,118) The oncogenic activity of 2-hydroxyglutarate has been attributed to its accumulation and the inhibitory effect on various…”
BackgroundEmerging roles for chromatin as a signal integration and storage platform
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l -2-Hydroxyglutarate: An Epigenetic Modifier and Putative Oncometabolite in Renal Cancer
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“Notably, both cell-free and in vitro studies demonstrate that the L enantiomer (L-2HG) is more potent at inhibiting 2OGDs including the TET enzymes(11, 12).”
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“However, 2-HG, particularly the ‘R’ enantiomer that is formed by the mutant IDH enzymes, is a poor inhibitor of the PHD enzymes [41].”
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“D2HG accumulates in glioma and AML patients whose malignancies bear IDH1 or IDH2 mutations and inhibits aKG-dependent dioxygenase activity by competing with aKG (Dang et al. 2009; Gross et al. 2010; Ward et al. 2010; Chowdhury et al. 2011; Xu et al. 2011).”
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“Although the function of the “oncometabolite” 2HG in the context of various cell types and tissues remains under active investigation, current evidence suggests that its major role is to competitively inhibit a-ketoglutarate-dependent enzymes that modify chromatin, particularly the TET family of DNA 5-methylcytosine h…”
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Metadata
- Authors
- Chowdhury, R., Yeoh, K. K., Tian, Y., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K. H., Li, X. S., Woon, E. C. Y., Yang, M., McDonough, M. A., King, O. N., Clifton, I. J., Klose, R. J., Claridge, T. D. W., Ratcliffe, P. J., Schofield, C. J., & Kawamura, A.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Schofield, Christopher J
- Kawamura, Akane
- ORCID
- Venue
- The EMBO Reports
- Published
- 2011-04-01
- Volume
- 12
- Issue
- 5
- Pages
- 463-469
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC3090014
- OpenAlex
- W2015755329
- Semantic Scholar
- e6bd34bdf5282202be386b2f353e072be7387c86
- Cited by
- 1,035
- References
- 31
- Citations by year
- 2026: 38 · 2025: 55 · 2024: 63 · 2023: 64 · 2022: 56 · 2021: 98 · 2020: 79 · 2019: 78 · 2018: 76 · 2017: 69 · 2016: 74 · 2015: 73 · 2014: 70 · 2013: 62 · 2012: 64
- FWCI
- 23.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- EMBO Reports (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Deutscher Akademischer Austauschdienst
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Keywords
- 2-hydroxyglutarate, oncometabolites, IDH mutation, histone lysine demethylases, JMJD2A, 2-oxoglutarate-dependent dioxygenase, HIF prolyl hydroxylase, histone methylation, enzyme inhibition
- MeSH terms
- Crystallography, Glutarates, Humans, Mixed Function Oxygenases, Isocitrate Dehydrogenase, Models, Molecular, Mutation, Neoplasms, Magnetic Resonance Spectroscopy, Procollagen-Proline Dioxygenase, Repressor Proteins, Mass Spectrometry, Signal Transduction, Inhibitory Concentration 50, Cell Line, Tumor, Histone Demethylases, Jumonji Domain-Containing Histone Demethylases
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