Cited by 1,035Cancer, Hypoxia, and MetabolismEpigenetics and DNA MethylationGlioma Diagnosis and Treatment

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

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Chowdhury, Rasheduzzaman, Yeoh, Kar Kheng, Tian, Ya‐Min, Hillringhaus, Lars, Bagg, Eleanor A, Rose, Nathan R, Leung, Ivanhoe K H, Li, Xuan S, Woon, Esther C Y, Yang, Ming, McDonough, Michael A, King, Oliver N, Clifton, Ian J, Klose, Robert J, Claridge, Timothy D W, Ratcliffe, Peter J, Schofield, Christopher J, Kawamura, Akane·2011·The EMBO Reports

DOI 10.1038/embor.2011.43PMC PMC3090014

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Abstract

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
“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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
None of the sources cited for this claim have been checked yet.
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
What the sources say
- Not checked yetcites Dang et al, 2009 source
- Not checked yetcites Ward et al, 2010 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes

Show all 21 claims

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
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It 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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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
Load-bearingStrength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably 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
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim.
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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.

23 of 23

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.”

3 of 3

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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…”
Background

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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: Chowdhury, Rasheduzzaman
Bagg, Eleanor A
Rose, Nathan R
Leung, Ivanhoe K H
Woon, Esther C Y
Yang, Ming
McDonough, Michael A
King, Oliver N
Clifton, Ian J
Klose, Robert J
Claridge, Timothy D W
Ratcliffe, Peter J
Schofield, Christopher J
Kawamura, Akane
Venue: The EMBO Reports
Publisher: Springer Science and Business Media LLC
Published: 2011-04-01
Volume: 12
Issue: 5
Pages: 463-469
ISSN: 1469-221X (ISSN-L)
1469-3178
DOI: 10.1038/embor.2011.43
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases

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