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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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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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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In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § DISCUSSION · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“We found this is the case (Fig 3F).”
§ The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases > R-/S-2HG.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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- It may state two separate claims as one. 19
- Probably not a substantial claim. 7
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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In the paper
“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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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.
None of the sources cited for this claim have been checked yet.
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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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § RESULTS · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
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
What the sources say
- Not checked yetcites Kaelin & Ratcliffe, 2008 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.”
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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
Semenza, G. L. (2010) · Oncogene · doi:10.1038/onc.2009.441 · Cited by 1,712
Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes
Dalgliesh, G. L., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C., et al. (2010) · Nature · doi:10.1038/nature08672 · Cited by 1,173
Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., et al. (2009) · Science · doi:10.1126/science.1170944 · Cited by 1,119
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Self-citationSomatic mutations of the histone H3K27 demethylase gene UTX in human cancer
van Haaften, G., Dalgliesh, G. L., Davies, H., Chen, L., Bignell, G., Greenman, C., Edkins, S., Hardy, C., O'Meara, S., Teague, J., et al. (2009) · Nature Genetics · doi:10.1038/ng.349 · Cited by 784
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Téllez-Plaza, M., Tang, W., Shang, Y., Umans, J. G., Francesconi, K. A., Goessler, W., Ledesma, M., León, M., Laclaustra, M., Pollak, J., et al. (2014) · Environmental Health Perspectives · doi:10.1289/ehp.1306674 · Cited by 120
“TET proteins were activated in the presence of high oxygen levels and alpha-ketoglutarate (α-KG), which is generated in citric acid cycle (Chowdhury et al. 2011; Xu et al. 2011).”
Metabostemness: A New Cancer Hallmark
Menéndez, J. A., & Alarcón, T. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00262 · Cited by 116
Micromanaging aerobic respiration and glycolysis in cancer cells
Orang, A., Petersen, J., McKinnon, R. A., & Michael, M. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.01.014 · Cited by 117
“miR-1827 MDM2 Colorectal Cancer S [98] miR-183 mTOR Neuropathic Pain S [99] miR-184 MYC Non-Small Cell Lung Cancer, Nasopharyngeal Carcinoma S [100,101] miR-185 MYC, PTEN, AKT Colorectal Cancer, Breast Cancer, Hepatocellular Carcinoma, Idiopathic Pulmonary Fibrosis, Non-Small Cell Lung Cancer S [102e104], [228,297]”
BackgroundChan, M. C., Ilott, N. E., Schödel, J., Sims, D., Tumber, A., Lippl, K., Mole, D. R., Pugh, C. W., Ratcliffe, P. J., Ponting, C. P., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.749291 · Cited by 113
“In Vitro Hydroxylation Assays—Inhibition assays for PHD1–3 were performed by MALDI-TOF MS using a Waters Micromass MALDI micro MX mass spectrometer via a modified version of the reported procedure (62).”
MethodSelf-citationAlterations in the placental methylome with maternal obesity and evidence for metabolic regulation
Mitsuya, K., Parker, A. N., Liu, L., Ruan, J., Vissers, M. C. M., & Myatt, L. (2017) · PLoS ONE · doi:10.1371/journal.pone.0186115 · Cited by 113
Kaminska, B., Czapski, B., Guzik, R., Król, S. K., & Gielniewski, B. (2019) · Molecules · doi:10.3390/molecules24050968 · Cited by 113
“Accumulation of 2-HG in cancer cells results in the complete inhibition of Jumonji-class histone demethylases [15,16].”
BackgroundIsocitrate dehydrogenase inhibitors in acute myeloid leukemia
Liu, X., & Gong, Y. (2019) · Biomarker Research · doi:10.1186/s40364-019-0173-z · Cited by 111
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CRL4VprBP E3 Ligase Promotes Monoubiquitylation and Chromatin Binding of TET Dioxygenases
Nakagawa, T., Lv, L., Nakagawa, M., Yu, Y., Yu, C. Y., D’Alessio, A. C., Nakayama, K., Fan, H., Chen, X., & Xiong, Y. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.12.002 · Cited by 114
“P A A uthor M anuscript Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.”
InfluentialMetabolic recoding of epigenetics in cancer
Wang, Y., & Lei, Q. (2018) · 癌症：英文版 · doi:10.1186/s40880-018-0302-3 · Cited by 109
The Metabolic Alterations of Cancer Cells
Sciacovelli, M., Gaude, E., Hilvo, M., & Frezza, C. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-416618-9.00001-7 · Cited by 108
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New Developments in the Pathogenesis and Therapeutic Targeting of the IDH1 Mutation in Glioma
Dimitrov, L., Hong, C. S., Yang, C., Zhuang, Z., & Heiss, J. D. (2015) · International Journal of Medical Sciences · doi:10.7150/ijms.11047 · Cited by 108
“It has been proposed that because R-2-HG is very similar structurally to a-KG, it may act as a direct competitive inhibitor of a-KG-dependent dioxygenases such as TET2 [59, 76, 77].”
BackgroundCancer Metabolism: Fueling More than Just Growth
Lee, N., & Kim, D. (2016) · Molecules and Cells · doi:10.14348/molcells.2016.0310 · Cited by 102
“…of 5-methylcytosine (3mC) hydroxylases (TETs) and the Jumonji C domain-containing histone lysine demethylases (KDMs), promoting hypermethylation (Chowdhury et al., 2011; Xu et al., 2011), which results in suppression of genes involved in cell differentiation (Losman et al., 2013; Lu et al.,…”
BackgroundThe paradox of mitochondrial dysfunction and extended longevity
Munkácsy, E., & Rea, S. L. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.03.016 · Cited by 103
TET-Mediated Hypermethylation Primes SDH-Deficient Cells for HIF2α-Driven Mesenchymal Transition
Morin, A., Goncalves, J., Moog, S., Castro‐Vega, L. J., Job, S., Buffet, A., Fontenille, M., Woszczyk, J., Gimenez‐Roqueplo, A., Letouzé, É., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.022 · Cited by 110
IDH inhibition in gliomas: from preclinical models to clinical trials
Rudà, R., Horbinski, C., van den Bent, M. J., Preusser, M., & Soffietti, R. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00967-7 · Cited by 105
Widespread bacterial lysine degradation proceeding via glutarate and L-2-hydroxyglutarate
Knorr, S., Sinn, M., Galetskiy, D., Williams, R. M., Wang, C., Müller, N., Mayans, O. M., Schleheck, D., & Hartig, J. S. (2018) · Nature Communications · doi:10.1038/s41467-018-07563-6 · Cited by 97
The oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to ferroptosis
Wang, T., Liang, J.-Y., Zhang, C., Xiong, Y., Guan, K., & Yuan, H. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1984-4 · Cited by 106
Challenges and Opportunities in Cancer Metabolomics
Kumar, A., & Misra, B. B. (2019) · PROTEOMICS · doi:10.1002/pmic.201900042 · Cited by 101
The oxygenase Jmjd6–a case study in conflicting assignments
Böttger, A., Islam, M. S., Chowdhury, R., Schofield, C. J., & Wolf, A. (2015) · Biochemical Journal · doi:10.1042/bj20150278 · Cited by 99
Self-citationVitamin C – A new player in regulation of the cancer epigenome
Gillberg, L., Ørskov, A. D., Liu, M., Harsløf, L. B. S., Jones, P. A., & Grønbæk, K. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.11.001 · Cited by 100
Metabolic Footprints and Molecular Subtypes in Breast Cancer
Cappelletti, V., Iorio, E., Miodini, P., Silvestri, M., Dugo, M., & Daidone, M. G. (2017) · Disease Markers · doi:10.1155/2017/7687851 · Cited by 99
“Accumulation of 2-HG is linked with a DNA hypermethylation phenotype [74, 77], and it is reported that 2-HG is an inhibitor of α-KG–dependent enzymes including PHD1-3, histone demethylase KDM4C, and 5-methylcytosine hydroxylases TET2 [78].”
BackgroundThe mitochondrial side of epigenetics
Castegna, A., Iacobazzi, V., & Infantino, V. (2015) · Physiological Genomics · doi:10.1152/physiolgenomics.00096.2014 · Cited by 100
“2-HG has two enantiomers, R-2HG and S-2HG, which inhibit TET activity, although to a different extent (23).”
BackgroundGlutamine Metabolism in Brain Tumors
Natarajan, S. K., & Venneti, S. (2019) · Cancers · doi:10.3390/cancers11111628 · Cited by 99
“D-2HG is structurally similar to α-ketoglutarate and inhibits α-KG-dependent enzymes, including histone and DNA demethylases [78,79].”
BackgroundGlioblastoma Therapy Can Be Augmented by Targeting IDH1-Mediated NADPH Biosynthesis
Wahl, D. R., Dresser, J., Wilder-Romans, K., Parsels, J. D., Zhao, S. G., Davis, M. A., Zhao, L., Kachman, M. T., Wernisch, S., Burant, C., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-2008 · Cited by 97
“Patients with this mutation exhibit DNA and histone hypermethylation and have an improved prognosis, while preclinical models of IDH1 mutant tumors suggest that they have depleted NADPH-dependent antioxidants and an increased sensitivity to radiation(46-50).”
The multifaceted contribution of α-ketoglutarate to tumor progression: An opportunity to exploit?
Abla, H., Sollazzo, M., Gasparre, G., Iommarini, L., & Porcelli, A. M. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.031 · Cited by 99
“lyzed hydroxylation in HIF-1α C-terminal transactivation domain [76,77].”
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Davis, M. I., Größ, S., Shen, M., Straley, K. S., Pragani, R., Lea, W., Popovici-Müller, J. V., DeLaBarre, B., Artin, E., Thorne, N., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.511030 · Cited by 93
“2-HG is thought to behave as an oncometabolite by inhibiting multiple -KG-dependent dioxygenases, which are important in a variety of biological processes, such as histone and DNA demethylation (8, 13).”
Lozoya, O. A., Martínez‐Reyes, I., Wang, T., Grenet, D., Bushel, P. R., Li, J., Chandel, N. S., Woychik, R. P., & Santos, J. H. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2005707 · Cited by 93
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“Interestingly, the oncometabolite produced by IDH1 mutations impairs histone demethylation, affecting UTX (H3K27me) and KDM4A/ JMJD2A (H3K36/K9me) resulting in a block to cell differentiation (12), further supporting a role in gliomas for altered methylation of these residues.”
BackgroundGlioblastoma Therapy in the Age of Molecular Medicine
Geraldo, L. H., Garcia, C., da Fonseca, A. C. C., Dubois, L. G., Spohr, T. C. L. D. S. E., Matias, D., Magalhães, E. S. D. C., do Amaral, R. F., da Rosa, B. G., Grimaldi, I., et al. (2018) · Trends in cancer · doi:10.1016/j.trecan.2018.11.002 · Cited by 93
The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer
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“D-2HG can competitively restrain α-KG-dependent dioxygenase enzymes, including DNA and histone demethylases [51-55].”
BackgroundClinical significance of T cell metabolic reprogramming in cancer
Herbel, C., Patsoukis, N., Bardhan, K., Seth, P., Weaver, J. D., & Boussiotis, V. A. (2016) · Clinical and Translational Medicine · doi:10.1186/s40169-016-0110-9 · Cited by 99
“In tumors with IDH1/2 mutations, high levels of fumarate, succinate, and 2HG have been reported, and these increases correlate with elevated histone methylation for H3K9 and H3K27, which are gene repressive marks [117].”
BackgroundThe Impact of DNA Methylation in Hematopoietic Malignancies
Guillamot, M., Cimmino, L., & Aifantis, I. (2016) · Trends in cancer · doi:10.1016/j.trecan.2015.12.006 · Cited by 96
“In normal cells the IDH enzymatic activity converts isocitrate to α-ketoglutarate (α-KG), an essential cofactor for TET proteins and other epigenetic regulators such as the histone demethylase family of Jumonji proteins [35].”
BackgroundSETting the Stage for Cancer Development: SETD2 and the Consequences of Lost MethylationPreprint
Fahey, C. C., & Davis, I. J. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026468 · Cited by 92
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ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming
Mishra, P., Tang, W., Putluri, V., Dorsey, T. H., Jin, F., Wang, F., Zhu, D., Amable, L., Deng, T., Zhang, S., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci93815 · Cited by 91
“2HG inhibits histone lysine demethylases, which can lead to increased methylation of histones (28, 29).”
BackgroundIsocitrate dehydrogenase mutations in gliomas
Guo, C., Pirozzi, C. J., Lopez, G. Y., & Yan, H. (2011) · Current Opinion in Neurology · doi:10.1097/wco.0b013e32834cd415 · Cited by 93
The Evolving Molecular Genetics of Low-grade Glioma
Venneti, S., & Huse, J. T. (2015) · Advances in Anatomic Pathology · doi:10.1097/pap.0000000000000049 · Cited by 90
The Activity of JmjC Histone Lysine Demethylase KDM4A is Highly Sensitive to Oxygen Concentrations
Hancock, R. L., Masson, N., Dunne, K., Flashman, E., & Kawamura, A. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.6b00958 · Cited by 89
Self-citationHyperpolarized [1-13C] Glutamate: A Metabolic Imaging Biomarker of IDH1 Mutational Status in Glioma
Chaumeil, M. M., Larson, P. E. Z., Woods, S. M., Cai, L., Eriksson, P., Robinson, A. E., Lupo, J., Vigneron, D. B., Nelson, S. J., Pieper, R. O., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0680 · Cited by 87
“Nonetheless, it is clear that 2-HG inhibits a range of α-KG-dependent dioxygenases, resulting in a broad range of alterations in the cellular epigenome (4, 5), which ultimately lead to oncogenesis (6-11).”
Rare insights into cancer biology
Adam, J., Yang, M., Soga, T., & Pollard, P. J. (2013) · Oncogene · doi:10.1038/onc.2013.222 · Cited by 90
Self-citationMolecular Pathways: Metabolic Control of Histone Methylation and Gene Expression in Cancer
Tran, T. Q., Lowman, X. H., & Kong, M. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2506 · Cited by 91
“2HG, a structural analogue of aKG, competitively inhibits many aKG-dependent enzymes, including histone demethylases, leading to histone hypermethylation and inhibition of cellular differentiation (31, 32).”
BackgroundMetformin as Potential Therapy for High-Grade Glioma
Mazurek, M., Litak, J., Kamieniak, P., Kulesza, B., Jonak, K. E., Baj, J., & Grochowski, C. (2020) · Cancers · doi:10.3390/cancers12010210 · Cited by 90
“IDH1 mutations result in the transformation of α-ketoglutarate to (D) -2-hydroxyglutarate, the accumulation of which leads to a disruption of the function of α-ketoglutarate-dependent enzymes resulting in hypermethylation of DNA and histones [76,77].”
BackgroundRecent advances of IDH1 mutant inhibitor in cancer therapy
Tian, W., Zhang, W., Wang, Y., Jin, R., Wang, Y., Guo, H., Tang, Y., & Yao, X. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.982424 · Cited by 88
Obstacles to Glioblastoma Treatment Two Decades after Temozolomide
Cruz, J. V. R., Batista, C., Afonso, B. D. H., Alexandre‐Moreira, M. S., Dubois, L. G., Pontes, B., Moura‐Neto, V., & Mendes, F. A. (2022) · Cancers · doi:10.3390/cancers14133203 · Cited by 92
Genetically-defined metabolic reprogramming in cancer
Mullen, A. R., & DeBerardinis, R. J. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.06.009 · Cited by 90
“These include the α-ketoglutarate-dependent dioxygenases, which comprise a large family of enzymes that carry out diverse functions such as prolyl hydroxylation, histone demethylation and epigenetic modification of DNA (Figure 2) [30, 31].”
BackgroundSadiku, P., Willson, J. A., Dickinson, R. S., Murphy, F. A., Harris, A. J., Lewis, A., Sammut, D., Mirchandani, A. S., Ryan, E. M., Watts, E., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90848 · Cited by 92
Self-citationJiang, L., Boufersaoui, A., Yang, C., Ko, B., Rakheja, D., Guevara, G., Hu, Z., & DeBerardinis, R. J. (2016) · Metabolic Engineering · doi:10.1016/j.ymben.2016.11.004 · Cited by 84
“Both D-2HG and L-2HG influence the activity of a large family of AKG-dependent dioxygenases, many of which function to demethylate histones and DNA, thereby epigenetically regulating gene expression (Chowdhury et al., 2011).”
BackgroundFriend or foe—IDH1 mutations in glioma 10 years on
Huang, L. E. (2019) · Carcinogenesis · doi:10.1093/carcin/bgz134 · Cited by 84
“In particular, histone demethylases are 200-fold more sensitive to D-2HG than EGLN, suggesting the involvement of IDH1R132H in chromatin remodeling (37).”
BackgroundMetabolite sensing and signaling in cancer
Wang, Y.-P., Li, J., Qu, J., Yin, M., & Lei, Q. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev119.007624 · Cited by 87
“In addition, 2HG suppresses histone demethylase KDM4C to enhance histoneH3 Lys-9methylation in glioma (16, 17).”
BackgroundChen, F., Bian, K., Tang, Q., Fedeles, B. I., Singh, V., Humulock, Z. T., Essigmann, J. M., & Li, D. (2017) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.7b00009 · Cited by 91
Digging deep into “dirty” drugs – modulation of the methylation machinery
Pleyer, L., & Greil, R. (2015) · Drug Metabolism Reviews · doi:10.3109/03602532.2014.995379 · Cited by 84
“Altered 2-HG/a-KG levels observed in cells with mutant IDH1/2 additionally result in the inhibition of the jumonjidomain-containing (JMJC) family of HDMs, another group of a-KG-dependent enzymes, which demethylate H3K9 and H3K26 (Chowdhury et al., 2011) (Figures 1B-III and 2A).”
BackgroundIDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?
Kayabölen, A., Yilmaz, E., & Onder, T. B. (2021) · Biomedicines · doi:10.3390/biomedicines9070799 · Cited by 88
“These mutations cause IDH1 and IDH2 to gain a neomorphic enzymatic function, by which they convert 2-OG produced by the wildtype IDH enzyme into D-2-hydroxyglutarate (2-HG) that is thought to be an oncometabolite [11]; it acts as an antagonist of 2-OG and therefore inhibits the enzymatic activities of 2-OG dependent e…”
BackgroundR-2-Hydroxyglutarate as the Key Effector of IDH Mutations Promoting Oncogenesis
Ye, D., Ma, S., Xiong, Y., & Guan, K. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.03.005 · Cited by 83
“Koivunen et al. (2012) had previously reported that S-2-HG inhibits EglN1, a member of the a-KG-dependent dioxygenases responsible for HIF-1a hydroxylation and degradation, whereas R-2-HG actually promotes EglN1 activity.”
BackgroundInfluentialInteractions between epigenetics and metabolism in cancers
Yun, J., Johnson, J. L., Hanigan, C. L., & Locasale, J. W. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00163 · Cited by 82
Epigenetic Therapies for Osteoarthritis
Grandi, F. C., & Bhutani, N. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.05.008 · Cited by 85
D-2-Hydroxyglutarate in Glioma Biology
Chou, F.-J., Liu, Y., Lang, F., & Yang, C. (2021) · Cells · doi:10.3390/cells10092345 · Cited by 87
“Several studies showed that tri-methylation of H3K4, H3K9 and H3K27 is present in IDH-mutated cancers [70,78].”
BackgroundOhba, S., Mukherjee, J., See, W. L., & Pieper, R. O. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0924 · Cited by 81
“Thea-KG generated in turn contributes to the production of NADPH in the citric acid cycle as well as to the activity of a-KG–dependent enzymes including the 5methylcytosine hydroxylases and histone methyltransferases that regulate the epigenetic state of the cell (7, 8).”
BackgroundA Cell‐Permeable Ester Derivative of the JmjC Histone Demethylase Inhibitor IOX1
Schiller, R., Scozzafava, G., Tumber, A., Wickens, J. R., Bush, J. T., Rai, G., Lejeune, C., Choi, H., Yeh, T., Chan, M. C., et al. (2014) · ChemMedChem · doi:10.1002/cmdc.201300428 · Cited by 81
Self-citationAutophagy and oxidative stress in gliomas with IDH1 mutations
Gilbert, M. R., Liu, Y., Neltner, J. H., Pu, H., Morris, A. J., Sunkara, M., Pittman, T. A., Kyprianou, N., & Horbinski, C. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1194-6 · Cited by 78
“Because 2-Hg is small and relatively polar, some prior studies have used esterified 2-Hg to improve in vitro cell permeability [6, 24, 38].”
Thompson, A. A. R., Dickinson, R. S., Murphy, F. A., Thomson, J. P., Marriott, H. M., Tavares, A., Willson, J. A., Williams, L., Lewis, A., Mirchandani, A. S., et al. (2017) · Science Immunology · doi:10.1126/sciimmunol.aal2861 · Cited by 78
Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases
Tarhonskaya, H., Rydzik, A. M., Leung, I. K. H., Loik, N. D., Chan, M. C., Kawamura, A., McCullagh, J. S. O., Claridge, T. D. W., Flashman, E., & Schofield, C. J. (2014) · Nature Communications · doi:10.1038/ncomms4423 · Cited by 80
Self-citationLi, H., Chawla, G., Hurlburt, A. J., Sterrett, M. C., Zaslaver, O., Cox, J. E., Karty, J. A., Rosebrock, A. P., Caudy, A. A., & Tennessen, J. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1614102114 · Cited by 76
“Staged time points are as follows: (1) embryos (Emb; 0–12 h after egg laying), (2) Emb (12–24 h after egg laying), (3) L1 larvae, (4) L2 larvae, (5) early-L3 larvae (0–12 h after L2-L3 molt), (6) mid-L3 larvae (24–36 h after L2-L3 molt), (7) wandering L3 larvae, (8) white prepupae (wpp), (9) adult females (3 d postecl…”
InfluentialMutations in the Isocitrate Dehydrogenase Genes IDH1 and IDH2 in Tumors
Schaap, F. G., French, P. J., & Bovée, J. V. M. G. (2012) · Advances in Anatomic Pathology · doi:10.1097/pap.0b013e31827b654d · Cited by 80
Androgen-regulated metabolism and biosynthesis in prostate cancer
Barfeld, S. J., Itkonen, H. M., Urbanucci, A., & Mills, I. G. (2014) · Endocrine Related Cancer · doi:10.1530/erc-13-0515 · Cited by 78
“Recently, mutations in iso-citrate dehydrogenases (IDH1 and IDH2) were reported, which result in the production of the ‘oncometabolite’ 2-hydroxyglutarate (Chowdhury et al. 2011).”
BackgroundEmerging Roles of ATRX in Cancer
Watson, L. A., Goldberg, H. E., & Bérubé, N. G. (2015) · Epigenomics · doi:10.2217/epi.15.82 · Cited by 82
Targeting Metabolism to Induce Cell Death in Cancer Cells and Cancer Stem Cells
Pecqueur, C., Oliver, L., Oizel, K., Lalier-Bretaudeau, L., & Vallette, F. M. (2013) · International Journal of Cell Biology · doi:10.1155/2013/805975 · Cited by 83
“Furthermore, the DNA repair enzyme MGMT (O6-methylguanine-methyltransferase) is usually overexpressed in these cells [88].”
BackgroundInfluentialGenetic and epigenetic alterations of myeloproliferative disorders
Feenstra, J. D. M., & Královics, R. (2012) · International Journal of Hematology · doi:10.1007/s12185-012-1235-2 · Cited by 81
“Increased 2HG levels can also lead to inhibition of histone demethylases [96], which may be an additional mechanism for leukemogenesis.”
BackgroundOperation of a TCA cycle subnetwork in the mammalian nucleus
Kafkia, E., Andrés‐Pons, A., Ganter, K., Seiler, M., Smith, T. S., Andrejeva, A., Jouhten, P., Pereira, F. M., Franco, C., Kuroshchenkova, A., et al. (2022) · Science Advances · doi:10.1126/sciadv.abq5206 · Cited by 76
Metabolic determinants of tumour initiation
Brunner, J. S., & Finley, L. W. S. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00773-5 · Cited by 78
OH, the Places You’ll Go! Hydroxylation, Gene Expression, and Cancer
Ploumakis, A., & Coleman, M. L. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.05.026 · Cited by 77
“Although an initial report suggested that IDH mutation was associated with HIF stabilization (Zhao et al., 2009), subsequent studies reported that D-2HG can promote PHD in vitro and reduce hypoxic HIFa induction in vivo (discussed in Losman and Kaelin, 2013).”
BackgroundInfluentialSulfur metabolism and its contribution to malignancy
Ward, N. P., & DeNicola, G. M. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.05.001 · Cited by 74
Dąbrowski, M. J., & Wojtaś, B. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20143478 · Cited by 73
“One of the most potent effects was observed for N-methyl lysine demethylase KDM4A (formerly known as JMJD2A) [74].”
BackgroundMetabolic Mechanisms of Epigenetic Regulation
Meier, J. L. (2013) · ACS Chemical Biology · doi:10.1021/cb400689r · Cited by 75
Mitochondrial determinants of cancer health disparities
Choudhury, A. R., & Singh, K. K. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.05.001 · Cited by 75
“Mutated forms of IDH convert isocitrate to 2-hydroxyglutarate, an oncometabolite that alters global gene expression patterns through DNA methylation and chromatin remodeling [71, 229].”
BackgroundKoivunen, P., & Laukka, T. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2721-8 · Cited by 76
Inhibition of a K9/K36 demethylase by an H3.3 point mutation found in paediatric glioblastoma
Voon, H. P. J., Udugama, M., Lin, W., Hii, L. L., Law, R. H. P., Steer, D. L., Das, P. P., Mann, J. R., & Wong, L. H. (2018) · Nature Communications · doi:10.1038/s41467-018-05607-5 · Cited by 79
Nakagawa, M., Nakatani, F., Matsunaga, H., Seki, T., Endo, M., Ogawara, Y., Machida, Y., Katsumoto, T., Yamagata, K., Hattori, A., et al. (2019) · Oncogene · doi:10.1038/s41388-019-0929-9 · Cited by 78
The Tricarboxylic Acid Cycle at the Crossroad Between Cancer and Immunity
Scagliola, A., Mainini, F., & Cardaci, S. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7974 · Cited by 75
“In such a way, IDH mutations progressively accumulate irreversible changes in the chromatin methylation landscape, altering normal cellular growth and differentiation programs (23, 65, 125).”
Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome
Napoli, E., Tassone, F., Wong, S., Angkustsiri, K., Simon, T. J., Song, G., & Giulivi, C. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.672360 · Cited by 71
“Epigenetics and 2HG in 22qDS—High 2HG concentrations are potentially interesting, because the D-isomer (D-2HG) may act as a competitive inhibitor of various KG-dependent enzymes, including the TET (ten-eleven translocation) family of 5-methylcytosine hydroxylases and the Jumonji-C domaincontaining histone demethylases…”
Chen, J.-Y., Lai, Y.-S., Tsai, H., Kuo, C.-C., Yen, B. L., Yeh, S., Sun, H. S., & Hung, W.-C. (2016) · Scientific Reports · doi:10.1038/srep32428 · Cited by 75
Xu, H., Sun, Y., You, B., Huang, C., Ye, D., & Chang, C. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.12.014 · Cited by 72
Epigenetics in T‐cell acute lymphoblastic leukemia
Peirs, S., der Meulen, J. V., de Walle, I. V., Taghon, T., Speleman, F., Poppe, B. G., & Vlierberghe, P. V. (2014) · Immunological Reviews · doi:10.1111/imr.12237 · Cited by 76
“Mutations in genes encoding for the cytosolic IDH1 or mitochondrial IDH2 have been identified in AML (56, 57) and result in the production of the oncometabolite 2-hydroxyglutarate, which inhibits the enzymatic activity of TET (58) and the Jumonji family of histone demethylases (59).”
BackgroundMetabolic plasticity and regulation of T cell exhaustion
Li, F., Liu, H., Zhang, D., Ma, Y., & Zhu, B. (2022) · Immunology · doi:10.1111/imm.13575 · Cited by 73
Biology of IDH mutant cholangiocarcinoma
Wu, M., Shi, L., Merritt, J., Zhu, A. X., & Bardeesy, N. M. (2022) · Hepatology · doi:10.1002/hep.32424 · Cited by 71
“4 mM IC50) [7,50,51] and the asparaginyl hydroxylase, hypoxia inducible factor 1 subunit alpha inhibitor, that regulate transcriptional activity of hypoxia- inducible factor 1 alpha subunit (HIF1A) (1500 ± 400 μM IC50) [6] (Figure 1).”
BackgroundInfluentialJin, Y., Elalaf, H., Watanabe, M., Tamaki, S., Hineno, S., Matsunaga, K., Woltjen, K., Kobayashi, Y., Nagata, S., Ikeya, M., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0131998 · Cited by 70
Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2
Borodovsky, A., Seltzer, M. J., & Riggins, G. J. (2011) · Current Opinion in Oncology · doi:10.1097/cco.0b013e32834d816a · Cited by 71
“Williams SC, Karajannis MA, Chiriboga L, et al. R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1alpha upregulation in adult glioma.”
BackgroundInfluentialUrban, D. J., Martinez, N. J., Davis, M. I., Brimacombe, K. R., Cheff, D. M., Lee, T. D., Henderson, M. J., Titus, S. A., Pragani, R., Rohde, J. M., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-12630-x · Cited by 71
“2-HG is structurally similar to α-KG and has been shown to inhibit α-KG-dependent enzymes, modifying the endogenous cellular biochemical balance (13).”
BackgroundMutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma
Spitzer, A., Gritsch, S., Nomura, M., Jucht, A., Fortin, J., Raviram, R., Weisman, H. R., Gonzalez Castro, L. N., Druck, N., Chanoch-Myers, R., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.03.008 · Cited by 69
Role of tyrosine phosphorylation in modulating cancer cell metabolism
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“titive inhibitor of α-KG-dependent dioxygenases [93].”
IDH1/IDH2 Inhibition in Acute Myeloid Leukemia
Cerchione, C., Romano, A., Daver, N. G., Dinardo, C. D., Jabbour, E. J., Konopleva, M. Y., Ravandi‐Kashani, F., Kadia, T. M., Martelli, M. P., Isidori, A., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.639387 · Cited by 73
Miller, J. J. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01238-3 · Cited by 70
“Specifically, D-2-HG acts as a competitive inhibitor of α-KG-dependent dioxygenases, which includes the teneleven translocation (TET) family of DNA hydrolases [7] and histone demethylases [8], both of which are critical for maintaining the epigenetic state of a cell.”
BackgroundJiang, H., Li, A. M., & Ye, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1004978 · Cited by 69
“The two enantiomers of 2-hydroxyglutarate (2-HG) exert similar effects on TET and other a-KG-dependent dioxygenases but are generated under different conditions.”
BackgroundInfluentialKhurshed, M., Molenaar, R. J., Lenting, K., Leenders, W. P. J., & Noorden, C. J. F. V. (2017) · Oncotarget · doi:10.18632/oncotarget.17106 · Cited by 72
Stuani, L., Riols, F., Millard, P., Sabatier, M., Batut, A., Saland, E., Viars, F., Tonini, L., Zaghdoudi, S., Linares, L. K., et al. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113325 · Cited by 72
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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