The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases

doi:10.1038/EMBOR.2011.43

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The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases

Journal Article•DOI•

The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases

Rasheduzzaman Chowdhury¹, Kar Kheng Yeoh¹, Ya-Min Tian¹, Lars Hillringhaus¹, Eleanor A.L. Bagg¹, Nathan R. Rose¹, Ivanhoe K. H. Leung¹, Xuan S Li¹, Esther C. Y. Woon¹, Ming Yang¹, Michael A. McDonough¹, Oliver N. King¹, Ian J. Clifton¹, Robert J. Klose¹, Timothy D. W. Claridge¹, Peter J. Ratcliffe¹, Christopher J. Schofield¹, Akane Kawamura¹ - Show less +14 more•Institutions (1)

University of Oxford¹

01 May 2011-EMBO Reports (John Wiley & Sons, Ltd)-Vol. 12, Iss: 5, pp 463-469

TL;DR: 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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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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Journal Article•DOI•

Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate

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Patrick S. Ward¹, Craig B. Thompson¹•Institutions (1)

Memorial Sloan Kettering Cancer Center¹

20 Mar 2012-Cancer Cell

TL;DR: It is argued that altered metabolism has attained the status of a core hallmark of cancer.

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2,623 citations

Cites background from "The oncometabolite 2-hydroxyglutara..."

...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)....
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...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)....
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Journal Article•DOI•

Fundamentals of cancer metabolism

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Ralph J. DeBerardinis¹, Navdeep S. Chandel²•Institutions (2)

University of Texas Southwestern Medical Center¹, Northwestern University²

01 May 2016-Science Advances

TL;DR: A conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis will progressively support the development of new strategies to treat human cancer.

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Abstract: Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

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1,850 citations

Journal Article•DOI•

Mitochondria and cancer

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Douglas C. Wallace¹•Institutions (1)

Children's Hospital of Philadelphia¹

01 Oct 2012-Nature Reviews Cancer

TL;DR: Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment and activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.

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Abstract: Contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Although mutations in mitochondrial genes are common in cancer cells, they do not inactivate mitochondrial energy metabolism but rather alter the mitochondrial bioenergetic and biosynthetic state. These states communicate with the nucleus through mitochondrial 'retrograde signalling' to modulate signal transduction pathways, transcriptional circuits and chromatin structure to meet the perceived mitochondrial and nuclear requirements of the cancer cell. Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment. These alterations activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.

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1,709 citations

Journal Article•DOI•

IDH mutation impairs histone demethylation and results in a block to cell differentiation

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Chao Lu¹, Patrick S. Ward¹, Patrick S. Ward², Gurpreet S. Kapoor², Dan Rohle¹, Dan Rohle³, Sevin Turcan¹, Omar Abdel-Wahab¹, Christopher R. Edwards², Raya Khanin¹, Maria E. Figueroa³, Ari Melnick³, Kathryn E. Wellen², Donald M. O'Rourke², Shelley L. Berger², Timothy A. Chan¹, Ross L. Levine¹, Ingo K. Mellinghoff³, Ingo K. Mellinghoff¹, Craig B. Thompson¹ - Show less +16 more•Institutions (3)

Memorial Sloan Kettering Cancer Center¹, University of Pennsylvania², Cornell University³

15 Feb 2012-Nature

TL;DR: It is reported that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells, and that inhibition of histone methylation can be sufficient to block the differentiation of non-transformed cells.

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Abstract: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.

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1,651 citations

Journal Article•DOI•

Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.

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Dominik Sturm¹, Hendrik Witt¹, Hendrik Witt², Volker Hovestadt¹, Dong Anh Khuong-Quang³, David T.W. Jones¹, Carolin Konermann¹, Elke Pfaff¹, Martje Tönjes¹, Martin Sill¹, Sebastian Bender¹, Marcel Kool¹, Marc Zapatka¹, Natalia Becker¹, Manuela Zucknick¹, Thomas Hielscher¹, Xiaoyang Liu³, Adam M. Fontebasso⁴, Marina Ryzhova, Steffen Albrecht⁴, Karine Jacob³, Marietta Wolter⁵, Martin Ebinger⁶, Martin U. Schuhmann⁶, Timothy E. Van Meter⁷, Michael C. Frühwald⁸, Holger Hauch, Arnulf Pekrun, Bernhard Radlwimmer¹, Tim Niehues⁹, Gregor Von Komorowski, Matthias Dürken, Andreas E. Kulozik², Jenny Madden¹⁰, Andrew M. Donson¹⁰, Nicholas K. Foreman¹⁰, Rachid Drissi¹¹, Maryam Fouladi¹¹, Wolfram Scheurlen⁹, Andreas von Deimling², Andreas von Deimling¹, Camelia M. Monoranu¹², Wolfgang Roggendorf¹², Christel Herold-Mende², Andreas Unterberg², Christof M. Kramm¹³, Jörg Felsberg⁵, Christian Hartmann¹⁴, Benedikt Wiestler², Wolfgang Wick², Till Milde¹, Till Milde², Olaf Witt², Olaf Witt¹, Anders Lindroth¹, Jeremy Schwartzentruber³, Damien Faury³, Adam Fleming³, Magdalena Zakrzewska¹⁵, Pawel P. Liberski¹⁵, Krzysztof Zakrzewski¹⁶, Peter Hauser¹⁷, Miklós Garami¹⁷, Almos Klekner¹⁸, László Bognár¹⁸, Sorana Morrissy¹⁹, Florence M.G. Cavalli¹⁹, Michael D. Taylor¹⁹, Peter van Sluis²⁰, Jan Koster²⁰, Rogier Versteeg²⁰, Richard Volckmann²⁰, Tom Mikkelsen²¹, Kenneth Aldape²², Guido Reifenberger⁵, V. Peter Collins²³, Jacek Majewski³, Andrey Korshunov¹, Peter Lichter¹, Christoph Plass¹, Nada Jabado³, Stefan M. Pfister², Stefan M. Pfister¹ - Show less +79 more•Institutions (23)

German Cancer Research Center¹, Heidelberg University², McGill University³, Montreal Children's Hospital⁴, University of Düsseldorf⁵, University of Tübingen⁶, Virginia Commonwealth University⁷, Augsburg College⁸, Boston Children's Hospital⁹, University of Colorado Denver¹⁰, Cincinnati Children's Hospital Medical Center¹¹, University of Würzburg¹², Martin Luther University of Halle-Wittenberg¹³, Hannover Medical School¹⁴, Medical University of Łódź¹⁵, Memorial Hospital of South Bend¹⁶, Semmelweis University¹⁷, University of Debrecen¹⁸, University of Toronto¹⁹, University of Amsterdam²⁰, Henry Ford Health System²¹, University of Texas MD Anderson Cancer Center²², University of Cambridge²³

16 Oct 2012-Cancer Cell

TL;DR: It is demonstrated that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup.

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1,557 citations

Cites background from "The oncometabolite 2-hydroxyglutara..."

...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) (Noushmehr et al....
[...]
...…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)…...
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Journal Article•DOI•

Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

[...]

Lenny Dang¹, David W. White¹, Stefan Gross¹, Bryson D. Bennett², Mark A. Bittinger¹, Edward M. Driggers¹, Valeria Fantin¹, Hyun Gyung Jang¹, Shengfang Jin¹, Marie C. Keenan¹, Kevin Marks¹, Robert M. Prins³, Patrick S. Ward⁴, Katharine E. Yen¹, Linda M. Liau³, Joshua D. Rabinowitz², Lewis C. Cantley⁵, Craig B. Thompson⁴, Matthew G. Vander Heiden⁶, Matthew G. Vander Heiden¹, Shinsan M. Su¹ - Show less +17 more•Institutions (6)

Agios Pharmaceuticals¹, Princeton University², University of California, Los Angeles³, University of Pennsylvania⁴, Beth Israel Deaconess Medical Center⁵, Massachusetts Institute of Technology⁶

10 Dec 2009-Nature

TL;DR: It is shown that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG), and that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.

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Abstract: Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.

...read moreread less

3,508 citations

"The oncometabolite 2-hydroxyglutara..." refers background in this paper

...However, they also cause a gain of function comprising catalysis of 2OG to the R -enantiomer of 2-hydroxyglutarate ( R -2HG...
[...]

Journal Article•DOI•

Oxygen Sensing by Metazoans: The Central Role of the HIF Hydroxylase Pathway

[...]

William G. Kaelin¹, Peter J. Ratcliffe²•Institutions (2)

Howard Hughes Medical Institute¹, University of Oxford²

23 May 2008-Molecular Cell

TL;DR: HIF plays a central role in the transcriptional response to changes in oxygen availability and is modulated by FIH1-mediated asparagine hydroxylation, and HIF-modulatory drugs are now being developed for diverse diseases.

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2,623 citations

"The oncometabolite 2-hydroxyglutara..." refers background in this paper

...…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)....
[...]
...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 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...
[...]

Journal Article•DOI•

The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate

[...]

Patrick S. Ward¹, Jay P. Patel², David R. Wise¹, Omar Abdel-Wahab², Bryson D. Bennett³, Hilary A. Coller³, Justin R. Cross¹, Valeria Fantin⁴, Cyrus V. Hedvat², Alexander E. Perl¹, Joshua D. Rabinowitz³, Martin Carroll¹, Shinsan M. Su⁴, Kim A. Sharp¹, Ross L. Levine², Craig B. Thompson¹ - Show less +12 more•Institutions (4)

University of Pennsylvania¹, Memorial Sloan Kettering Cancer Center², Princeton University³, Agios Pharmaceuticals⁴

16 Mar 2010-Cancer Cell

TL;DR: It is reported that tumor 2HG is elevated in a high percentage of patients with cytogenetically normal acute myeloid leukemia (AML), and AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities, potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis.

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1,790 citations

"The oncometabolite 2-hydroxyglutara..." refers background in this paper

...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)....
[...]
...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 high concentrations of R-2HG (more than 10 mM) that have been observed in malignant brain tumours and leukaemias (Dang et al, 2009; Gross et al, 2010; Ward et al, 2010), might be sufficient to inhibit even the less-susceptible 2OG oxygenases....
[...]

Journal Article•DOI•

Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase

[...]

Mary A. Selak, Sean M. Armour¹, Elaine D. MacKenzie, Houda Boulahbel, David G. Watson², Kyle D. Mansfield¹, Yi Pan¹, M. Celeste Simon¹, Craig B. Thompson¹, Eyal Gottlieb - Show less +6 more•Institutions (2)

University of Pennsylvania¹, University of Strathclyde²

01 Jan 2005-Cancer Cell

TL;DR: A mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events is described, suggesting a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.

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1,723 citations

"The oncometabolite 2-hydroxyglutara..." refers background in this paper

...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....
[...]

Journal Article•DOI•

Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics

[...]

Gregg L. Semenza¹•Institutions (1)

Johns Hopkins University School of Medicine¹

04 Feb 2010-Oncogene

TL;DR: This review summarizes the current state of knowledge regarding the molecular mechanisms by which Hif-1 contributes to cancer progression, focusing on clinical data associating increased HIF-1 levels with patient mortality and pharmacological data showing anticancer effects of H IF-1 inhibitors in mouse models of human cancer.

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Abstract: Adaptation of cancer cells to their microenvironment is an important driving force in the clonal selection that leads to invasive and metastatic disease. O2 concentrations are markedly reduced in many human cancers compared with normal tissue, and a major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by hypoxia-inducible factor 1 (HIF-1). This review summarizes the current state of knowledge regarding the molecular mechanisms by which HIF-1 contributes to cancer progression, focusing on (1) clinical data associating increased HIF-1 levels with patient mortality; (2) preclinical data linking HIF-1 activity with tumor growth; (3) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology and (4) pharmacological data showing anticancer effects of HIF-1 inhibitors in mouse models of human cancer.

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1,549 citations