Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors
Open accessAbstract
Two Krebs cycle genes, fumarate hydratase ( FH ) and succinate dehydrogenase ( SDH ), are mutated in a subset of human cancers, leading to accumulation of their substrates, fumarate and succinate, respectively. Here we demonstrate that fumarate and succinate are competitive inhibitors of multiple α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases, and the TET (ten-eleven translocation) family of 5-methlycytosine (5mC) hydroxylases. Knockdown of FH and SDH results in elevated intracellular levels of fumarate and succinate, respectively, which act as competitors of α-KG to broadly inhibit the activity of α-KG-dependent dioxygenases. In addition, ectopic expression of tumor-derived FH and SDH mutants inhibits histone demethylation and hydroxylation of 5mC. Our study suggests that tumor-derived FH and SDH mutations accumulate fumarate and succinate, leading to enzymatic inhibition of multiple α-KG-dependent dioxygenases and consequent alterations of genome-wide histone and DNA methylation. These epigenetic alterations associated with mutations of FH and SDH likely contribute to tumorigenesis.
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Written from the paper’s full text.
TL;DR
Fumarate and succinate, which accumulate when FH or SDH is lost, act as α-KG competitors and suppress multiple α-KG-dependent dioxygenases, including histone demethylases and TET DNA hydroxylases. This connects FH/SDH mutations to broad histone and DNA methylation changes that may contribute to tumorigenesis.
Key findings
- In vitro, fumarate and succinate inhibited CeKDM7A by more than 80% at 1–10 mM; for HsKDM4A, fumarate caused 22%, 41%, and 73% inhibition and succinate caused 43%, 68%, and 85% inhibition at 1, 3, and 10 mM, with succinate more potent (IC50 0.8 mM) than fumarate (IC50 1.5 mM).
- In cultured cells, cell-permeable fumarate or succinate increased H3K4 monomethylation about fourfold, H3K27 and H3K79 dimethylation about fourfold and threefold, and H3K4 trimethylation about twofold; FH or SDHA/B knockdown increased histone methylation three- to fivefold, raised HIF1α about fivefold, and lowered endostatin about sevenfold, effects diminished by cell-permeable α-KG.
- TET-catalyzed 5hmC production was reduced in FH, SDHA, or SDHB knockdown cells by 71%, 73%, and 82% for TET1 and by 80%, 83%, and 69% for TET2; in mouse liver, Fh or Sdha knockdown reduced 5hmC by 72% and 63% and increased Hoxa gene expression more than tenfold.
- Tumor-derived mutants were impaired: FH R190H and H137R retained 17% and 10% of wild-type activity; SDHA G555E and R554W retained 51% and 46%; SDHB R46Q and A43P retained 48% and 61%; wild-type but not mutant re-expression restored demethylation and 5hmC and reduced fumarate/succinate.
Methods
- In vitro demethylase assays used synthetic H3K9me1 and H3K36me3 peptides with MALDI-TOF/TOF mass spectrometry; FH and SDH enzyme activities were measured by absorbance-based assays.
- Cell work used HeLa and HEK293T cells with siRNA or stable knockdown of FH, SDHA, or SDHB, treatment with cell-permeable fumarate/succinate or octyl-α-KG, and TET1/TET2 catalytic-domain expression; readouts included GC-MS, Western blot, immunofluorescence, dot blot, and quantitative RT-PCR.
- In vivo work used hydrodynamic tail-vein siRNA delivery to knock down mouse liver Fh or Sdha (n = 3 per group); statistics used two-tailed unpaired Student’s t-test, triplicate experiments, and P < 0.05.
Limitations
- The paper notes an alternative product-inhibition model, observes that the succinate/α-KG ratio did not change in cells expressing tumor-derived FH mutants, and states that FH/SDH tumorigenesis may involve mechanisms independent of α-KG-dependent dioxygenases; it also says fumarate-mediated KEAP1 succination and NRF2 signaling require further exploration.
- The corrigendum reports that Figure 2B mislabeled SDHA and SDHB as FH and duplicated an actin control, though the authors state this does not affect the conclusions.
- Evident from the text: TET inhibition is inferred mainly from 5hmC readouts rather than direct TET enzyme kinetics, and the study relies on knockdown/overexpression and cell-permeable metabolite esters rather than direct human tumor metabolite-epigenome correlations.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Findingown data
Fumarate and succinate act as competitive inhibitors of several α-ketoglutarate-dependent dioxygenases, including histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases, and TET 5-methylcytosine hydroxylases.
“Here we demonstrate that fumarate and succinate are competitive inhibitors of multiple a-ketoglutarate (a-KG)dependent dioxygenases, including histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases, and the TET (ten-eleven translocation) family of 5-methlycytosine (5mC) hydroxylases.”
Quote in the paperSubstantial claim - Findingown data
Ectopic expression of tumor-derived FH and SDH mutants inhibits histone demethylation and 5mC hydroxylation.
“ectopic expression of tumor-derived FH and SDH mutants inhibits histone demethylation and hydroxylation of 5mC.”
Quote in the paperSubstantial claim - Findingown data
Fumarate and succinate inhibit the demethylase activity of human KDM4A (HsKDM4A) on trimethylated H3K36.
“Fumarate and succinate inhibit the demethylase activity of human KDM4A (HsKDM4A) toward trimethylated H3K36, determined by mass spectrometry (MS) assay as in B.”
Quote in the paperSubstantial claim - Findingown data
Wild-type FH, SDHA, or SDHB, but not their tumor-derived mutants, rescues the reduction of 5hmC in FH or SDH knockdown cells.
“Cotransfection with wild-type FH, SDHA, or SDHB, but not their mutants (i.e., FH R190H , SDHA G555E , or SDHB R46Q ), could rescue the reduction of 5hmC levels in FH or SDH stable knockdown cells”
Quote in the paperSubstantial claim - Findingown data
Knockdown of FH or SDH decreases TET-catalyzed production of 5-hydroxymethylcytosine in cultured cells.
“Knocking down FH or SDH reduces the TET-catalyzed 5hmC production in cultured cells.”
Quote in the paperSubstantial claim
- Findingown data
In cultured cells, fumarate and succinate increase histone methylation across the genome.
“Fumarate and succinate increase genome-wide histone methylations, accumulate HIF1a, and reduce endostatin in cultured cells.”
Quote in the paperSubstantial claim - Findingown data
In HEK293T and HeLa cells, cell-permeable fumarate at 2.5 mM or succinate at 5 mM reduces endostatin levels.
“Cell-permeable fumarate (2.5 mM) or succinate (5 mM) increases histone methylation and HIF1a and reduces endostatin in HEK293T cells (left) and HeLa cells (right), as determined by Western-blot.”
Quote in the paperSubstantial claim - Findingown data
In HEK293T cells with knockdown of FH, SDHA, or SDHB, cell-permeable octyl-α-ketoglutarate at 5 mM reduces the accumulation of HIF1α caused by FH or SDH suppression.
“Cell-permeable octyl-a-KG (5mM) diminishes the effect of FH or SDH suppression on increasing histone methylations, accumulating HIF1a, and decreasing endostatin in HEK293T cells with knockdown of FH (left panel), SDHA (middle panel), and SDHB (right panel), as determined by Western blot.”
Quote in the paperSubstantial claim - Findingown data
In vitro, fumarate and succinate inhibit the activity of α-ketoglutarate-dependent lysine demethylases.
“Fumarate and succinate inhibit the activity of a-KG-dependent KDMs in vitro.”
Quote in the paperSubstantial claim - Findingown data
Succinate inhibits HsKDM4A more potently than fumarate does.
“Succinate is more potent to inhibit HsKDM4A than fumarate.”
Quote in the paperSubstantial claim - Findingown data
In HEK293T and HeLa cells, cell-permeable fumarate at 2.5 mM or succinate at 5 mM increases histone methylation.
“Cell-permeable fumarate (2.5 mM) or succinate (5 mM) increases histone methylation and HIF1a and reduces endostatin in HEK293T cells (left) and HeLa cells (right), as determined by Western-blot.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of tumor-derived FH or SDHA/B mutants inhibits histone demethylation.
“Overexpression of tumor-derived FH or SDHA/B mutants inhibits histone demethylation and hydroxylation of prolyl residues.”
Quote in the paperSubstantial claim - Findingown data
In cultured cells, fumarate and succinate reduce endostatin levels.
“Fumarate and succinate increase genome-wide histone methylations, accumulate HIF1a, and reduce endostatin in cultured cells.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of TET1-CD or TET2-CD fails to increase 5hmC in HEK293 cells with stable knockdown of FH or SDHA/B.
“overexpression of TET1-CD or TET2-CD was ineffective to increase 5hmC in HEK293 cells with stable knockdown of FH or SDHA/B”
Quote in the paperSubstantial claim - Findingown data
The ratio of succinate to α-ketoglutarate is increased in cells that express certain tumor-derived SDH mutants, such as SDHA R554W or SDHB A43P.
“In this study, we show that the succinate/a-KG ratio is elevated in cells expressing several tumor-derived SDH mutants (e.g., SDHA R554W or SDHB A43P ).”
Quote in the paperSubstantial claim - Findingown data
In HEK293T cells with knockdown of FH, SDHA, or SDHB, cell-permeable octyl-α-ketoglutarate at 5 mM reduces the increase in histone methylation caused by FH or SDH suppression.
“Cell-permeable octyl-a-KG (5mM) diminishes the effect of FH or SDH suppression on increasing histone methylations, accumulating HIF1a, and decreasing endostatin in HEK293T cells with knockdown of FH (left panel), SDHA (middle panel), and SDHB (right panel), as determined by Western blot.”
Quote in the paperSubstantial claim - Findingown data
In HEK293T and HeLa cells, cell-permeable fumarate at 2.5 mM or succinate at 5 mM increases HIF1α levels.
“Cell-permeable fumarate (2.5 mM) or succinate (5 mM) increases histone methylation and HIF1a and reduces endostatin in HEK293T cells (left) and HeLa cells (right), as determined by Western-blot.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of tumor-derived FH or SDHA/B mutants inhibits TET-catalyzed oxidation of 5-methylcytosine.
“Overexpression of tumor-derived FH or SDHA/B mutants inhibits the TET-catalyzed 5mC oxidation.”
Quote in the paperSubstantial claim - Findingown data
In vivo, knockdown of Fh or Sdha inhibits multiple α-ketoglutarate-dependent dioxygenases.
“Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates gene expression in vivo.”
Quote in the paperSubstantial claim - Findingown data
CeKDM7A demethylates H3K9me1 to H3K9me0 at a near-physiological α-KG concentration of 15 mM.
“Mass spectrometric analysis demonstrated that a near-physiological a-KG concentration of 15 mM could support substrate demethylation (from H3K9me1 to H3K9me0) by CeKDM7A”
Quote in the paperSubstantial claim - Findingown data
In HEK293T cells with knockdown of FH, SDHA, or SDHB, cell-permeable octyl-α-ketoglutarate at 5 mM reduces the decrease in endostatin caused by FH or SDH suppression.
“Cell-permeable octyl-a-KG (5mM) diminishes the effect of FH or SDH suppression on increasing histone methylations, accumulating HIF1a, and decreasing endostatin in HEK293T cells with knockdown of FH (left panel), SDHA (middle panel), and SDHB (right panel), as determined by Western blot.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of tumor-derived FH or SDHA/B mutants inhibits hydroxylation of prolyl residues.
“Overexpression of tumor-derived FH or SDHA/B mutants inhibits histone demethylation and hydroxylation of prolyl residues.”
Quote in the paperSubstantial claim - Findingnone given
In cells expressing tumor-derived FH mutants, the succinate/α-ketoglutarate ratio remains unchanged.
“However, the succinate/ a-KG ratio is not changed in cells expressing tumorderived FH mutants”
Quote in the paperSubstantial claim - Findingown data
In cultured cells, fumarate and succinate cause accumulation of HIF1α.
“Fumarate and succinate increase genome-wide histone methylations, accumulate HIF1a, and reduce endostatin in cultured cells.”
Quote in the paperSubstantial claim - Findingown data
Fumarate and succinate act as antagonists of α-ketoglutarate and broadly inhibit α-ketoglutarate-dependent dioxygenases, including JMJD-family lysine demethylases and TET-family 5-methylcytosine hydroxylases.
“Fumarate and succinate can function as a-KG antagonists to broadly inhibit a-KG-dependent dioxygenases, including the JMJD family KDMs and the TET family of 5mC hydroxylases.”
Quote in the paperSubstantial claim - Findingown data
Fumarate and succinate inhibit the demethylase activity of C. elegans KDM7A (CeKDM7A).
“Fumarate and succinate inhibit the demethylase activity of C. elegans KDM7A (CeKDM7A).”
Quote in the paperSubstantial claim - Findingown data
In cultured cells, ectopic expression of tumor-derived FH or SDH mutants inhibits α-ketoglutarate-dependent dioxygenases.
“Ectopic expression of tumor-derived FH or SDH mutants inhibits a-KG-dependent dioxygenases in cultured cells.”
Quote in the paperSubstantial claim - Findingown data
In vivo, knockdown of Fh or Sdha regulates gene expression.
“Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates gene expression in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
The elevated fumarate and succinate caused by FH/SDH knockdown compete with α-KG and broadly inhibit α-KG-dependent dioxygenases.
“which act as competitors of a-KG to broadly inhibit the activity of a-KG-dependent dioxygenases.”
Quote in the paperSubstantial claim - Premisecitation
Six genes encoding FH and SDH subunits are mutated germinally and somatically in several human cancers.
“Besides IDH1 and IDH2, six genes (FH, SDHA, SDHB, SDHC, SDHD, and SDHAF2), encoding for the subunits of two different Krebs cycle enzymes (FH and SDH), are mutated both germinally and somatically in a number of human cancers”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Baysal et al. 2000
Not checked in the free run.
- cites Astuti et al. 2001
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- cites Oermann et al. 2012
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- Premisecitation
Alterations of Fe(II)/α-KG-dependent dioxygenases contribute to tumorigenesis.
“Accumulating genetic and biochemical evidence supports the notion that the alterations of Fe (II)/ a-KG-dependent dioxygenases contribute to tumorigenesis”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Oermann et al. 2012
Not checked in the free run.
- Interpretationreasoning
The epigenetic changes associated with FH and SDH mutations probably promote tumorigenesis.
“These epigenetic alterations associated with mutations of FH and SDH likely contribute to tumorigenesis.”
Quote in the paperSubstantial claim - Premisecitation
Fe(II)/α-KG-dependent dioxygenases hydroxylate diverse substrates, including 5-methylcytosine in genomic DNA.
“Fe(II)/a-KG-dependent dioxygenases are present in all living organisms and catalyze hydroxylation reactions on a diverse set of substrates, including proteins, alkylated DNA/RNA, lipids, antibiotics, and, most recently, 5-methylcytosine (5mC) of genomic DNA”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Hausinger 2004
Not checked in the free run.
- cites Loenarz and Schofield 2008
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- cites Tahiliani et al. 2009
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- Premisecitation
Mutations in certain metabolic enzymes can play a causal role in tumorigenesis.
“Several lines of evidence, including the recent identification of mutations affecting isocitrate dehydrogenase (IDH), fumarate hydratase (FH), and succinate dehydrogenase (SDH), have demonstrated that mutations in certain metabolic enzymes may play a causal role in tumorigenesis.”
Quote in the paperSubstantial claim - Premisecitation
Most tumor-derived FH or SDH mutations cause loss of function such as truncation or frameshift, eliminating enzyme activity.
“Most tumor-derived mutations targeting FH or SDH genes cause obvious loss of function such as truncation or frameshift (Alam et al. 2005;Bayley et al. 2008;Bardella et al. 2011), which would eliminate the activity of FH or SDH enzymes.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Alam et al. 2005
Not checked in the free run.
- cites Bayley et al. 2008
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- cites Bardella et al. 2011
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- Interpretationown data
Fumarate and succinate compete with α-KG to broadly inhibit α-KG-dependent dioxygenases, including KDMs, PHDs, and C-P4Hs.
“Together, our results demonstrate that fumarate and succinate act as competitors of a-KG to broadly inhibit the activity of a-KG-dependent dioxygenases, including KDMs, PHDs and C-P4Hs.”
Quote in the paperSubstantial claim - Interpretationown data
Fumarate and succinate act as α-KG antagonists to broadly inhibit α-KG-dependent dioxygenases beyond PHDs, including JMJD KDMs and TET 5mC hydroxylases.
“We show here that fumarate and succinate can also function as a-KG antagonists to broadly inhibit a-KG-dependent dioxygenases besides PHDs, including the JMJD family KDMs and the TET family of 5mC hydroxylases”
Quote in the paperSubstantial claim - Interpretationreasoning
A general paradigm is that changes in metabolic intermediates caused by mutations in metabolic tumor suppressors mediate the tumor-suppressive effects of those mutations.
“A common paradigm emerges that alteration of metabolic intermediates caused by mutations in metabolic tumor suppressors is responsible for the tumor suppression effect of metabolic enzyme mutations.”
Quote in the paperSubstantial claim - Interpretationreasoning
The study indicates a reverse regulatory mechanism in which metabolism controls transcription through altered levels of intermediates like fumarate and succinate, affecting gene expression via epigenetic modifications.
“However, our study also suggests a reciprocal mechanism: regulation of transcription by metabolism via the changing levels of metabolic intermediates-such as fumarate and succinate-that influence gene expression by epigenetic modifications.”
Quote in the paperSubstantial claim - Interpretationown data
Tumor-derived FH and SDH mutants are not functional in fumarate or succinate metabolism.
“Together, these results indicate that the tumor-derived FH and SDH mutants are not functional in fumarate or succinate metabolism.”
Quote in the paperSubstantial claim - Interpretationown data
Fumarate and succinate accumulation inhibits KDMs in mouse liver cells in vivo.
“These data suggest that accumulation of fumarate and succinate can inhibit KDMs in mouse liver cells in vivo.”
Quote in the paperSubstantial claim - Premisereasoning
Fumarate and succinate are structurally similar to α-KG and 2-HG, sharing the acetate end and two oxygen atoms linked to C-5 that interact with conserved dioxygenase residues.
“Structurally, both fumarate and succinate are similar to a-KG and 2-HG.They have the same acetate end and include two oxygen atoms linked to C-5 that are used by a-KG and 2-HG to interact with conserved residues in the dioxygenases”
Quote in the paperSubstantial claim - Interpretationreasoning
Inhibition of TET family enzymes may contribute to tumorigenesis in FH or SDH mutant cancer.
“Given the well-characterized tumor suppressor function of TET, we propose that inhibition of the TET family enzymes may contribute to tumorigenesis of FH or SDH mutant cancer.”
Quote in the paperSubstantial claim- Rests on an assumption: TET family enzymes function as tumor suppressors.
- Interpretationreasoning
For IDH, FH, and SDH mutations, the shared targets are α-ketoglutarate-dependent dioxygenases, which include both lysine demethylases and DNA demethylases.
“For the group of IDH, FH, and SDH, the common targets are the a-KG-dependent dioxygenases, including both KDMs and DNA demethylases.”
Quote in the paperSubstantial claim - Interpretationown data
Product inhibition is unlikely to account for the reduced activity of α-ketoglutarate-dependent dioxygenases in cells with FH mutations.
“suggesting that the product inhibition mechanism may not explain the impairment of a-KG-dependent dioxygenases in FH mutated cells.”
Quote in the paperSubstantial claim - Interpretationreasoning
Accumulation of fumarate or succinate in cancer cells with FH or SDH mutations may alter epigenetic DNA modification by inhibiting TETs.
“Accumulation of fumarate or succinate in cancer cells containing FH or SDH mutations may contribute to alterations of epigenetic DNA modification via inhibiting TETs.”
Quote in the paperSubstantial claim
- May combine two claims. 30
- The quote only partly states this claim. 6
- Classified as probably not a substantial claim. 6
May combine two claims.
Findingown dataReducing FH or SDH expression raises intracellular fumarate or succinate levels, respectively.
“Knockdown of FH and SDH results in elevated intracellular levels of fumarate and succinate, respectively”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataKnockdown of FH, SDHA, or SDHB reduces TET1-induced 5hmC by 71%, 73%, and 82%, and TET2-induced 5hmC by 80%, 83%, and 69%, respectively.
“Knockdown of FH, SDHA, and SDHB reduced TET1-induced 5hmC levels by 71%, 73%, and 82%, respectively, as compared with control cells coinfected with retrovirus containing the control shRNA vector pMKO.”
- Also stated in: § Suppression of FH or SDH expression reduces TET-catalyzed 5hmC production in cultured cells · plain
“A virtually identical result was obtained for TET2-catalyzed 5hmC production, which was also decreased by 80%, 83% and 69% in cells with stable knockdown of FH, SDHA, and SDHB, respectively.”
Quote in the paperSubstantial claim- Also stated in: § Suppression of FH or SDH expression reduces TET-catalyzed 5hmC production in cultured cells · plain
May combine two claims.
Findingown dataTransient knockdown of Fh and Sdha in mouse liver reduces their mRNA by 62% and 78% and their proteins by threefold and twofold, respectively.
“At 12-h after siRNA injection, we were able to achieve 62% and 78% reduction of Fh and Sdha mRNA expression, respectively, in mouse livers”
- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · plain
“hepatic expression of Fh and Sdha proteins was decreased by threefold and twofold, respectively”
Quote in the paperSubstantial claim- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · plain
May combine two claims.
Findingown dataTumor-derived FH and SDH mutants have reduced enzyme activity: FH R190H and H137R at 17% and 10% of wild-type; SDHA G555E and R554W at 51% and 46%; SDHB R46Q and A43P at 48% and 61%.
“the activity of FH R190H (the most frequent mutation in hereditary leiomyomatosis and renal cell cancer [HLRCC] patients) and FH H137R is only 17% and 10%, respectively, of wild-type FH”
- Also stated in: § Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases · plain
“The activity of tumor-derived mutants SDHA G555E and SDHA R554W is 51% and 46%, respectively, of wild-type SDHA, and the activity of SDHB R46Q (the most frequent SDHB mutation in paraganglioma) and SDHB A43P mutants is 48% and 61%, respectively, of wild-type SDHB.”
Quote in the paperSubstantial claim- Also stated in: § Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases · plain
May combine two claims. The quote only partly states this claim.
Findingown dataCell-permeable methyl-fumarate and methyl-succinate increase intracellular fumarate and succinate and elevate fumarate/α-KG and succinate/α-KG ratios.
“addition of 2.5 mM methyl-fumarate and 5 mM methyl-succinate to the cultured HeLa cells resulted in a significant increase of intracellular fumarate and succinate, respectively, as determined by gas chromatography-mass spectrometry (GC-MS)”
- Also stated in: § Both fumarate and succinate increase genome-wide histone methylations, accumulate HIF1a, and reduce endostatin in cultured cells · plain
“The fumarate/ a-KG and succinate/a-KG ratios were elevated in these cells”
Quote in the paperSubstantial claim- Also stated in: § Both fumarate and succinate increase genome-wide histone methylations, accumulate HIF1a, and reduce endostatin in cultured cells · plain
May combine two claims. The quote only partly states this claim.
Findingown dataFumarate or succinate at 1, 3, and 10 mM inhibits CeKDM7A by more than 80%, and higher α-KG reduces this inhibition.
“Addition of 1 mM, 3 mM, and 10 mM fumarate resulted in >80% inhibition of CeKDM7A”
- Also stated in: § Both fumarate and succinate inhibit the activity of a-KG-dependent KDMs in vitro · plain
“inhibition of CeKDM7A by fumarate or succinate became less effective, along with increased concentrations of a-KG”
Quote in the paperSubstantial claim- Also stated in: § Both fumarate and succinate inhibit the activity of a-KG-dependent KDMs in vitro · plain
May combine two claims.
Findingown dataTransient knockdown of Fh or Sdha decreases 5hmC in mouse liver cells, with 5hmC production reduced by 72% and 63%, respectively.
“Transient knockdown of Fh or Sdha by siRNA significantly decreased 5hmC in liver cells, especially near hepatic portal veins”
- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · boosted
“a dot blot assay demonstrated that 5hmC production was decreased by 72% and 63% in the livers of Fh and Sdha siRNA knockdown mice, respectively”
Quote in the paperSubstantial claim- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · boosted
May combine two claims.
Findingown dataCell-permeable fumarate and succinate increase H3K4 monomethylation, H3K27 and H3K79 dimethylation, and H3K4 trimethylation in cultured cells.
“Cell-permeable fumarate and succinate increased H3K4 monomethylation (by fourfold), H3K27 and H3K79 dimethylation (by fourfold and threefold, respectively), and H3K4 trimethylation (by twofold)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datasiRNA depletion of FH and SDHA/B elevates fumarate and succinate and increases histone methylation, HIF1α, and decreases endostatin in HeLa cells.
“depletion of FH and SDHA/B by siRNA resulted in elevated levels of fumarate and succinate in HeLa cells, as determined by GC-MS assay”
- Also stated in: § Fumarate and succinate alter epigenetics · plain
“Knocking down FH and SDHA/B resulted in a significant increase of histone methylations on H3K4, H3K9, and H3K79 (by threefold to fivefold); accumulation of HIF1a (by fivefold); and a decrease of endostatin (by sevenfold)”
Quote in the paperSubstantial claim- Also stated in: § Fumarate and succinate alter epigenetics · plain
May combine two claims.
Findingown dataKnockdown of FH or SDHA/B upregulates HOXA genes; wild-type FH or SDH reduces HOXA expression, while mutant FH or SDH has no effect or increases it.
“knockdown of FH or SDHA/B resulted in up-regulation of several HOXA genes (e.g., HOXA2, HOXA4, and HOXA5)”
- Also stated in: § Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases · plain
“Re-expression of wild-type FH or SDH reduced HOXA gene expression to the control levels.”
- Also stated in: § Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases · plain
“In contrast, re-expression of mutant FH or SDH had no effect or even increased HOXA gene expression”
Quote in the paperSubstantial claim- Also stated in: § Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases · plain
Probably not a substantial claim: may not pass S1 (asserted), S4 (based). May combine two claims. The quote only partly states this claim.
Findingown dataFh or Sdha knockdown in mouse liver increases histone methylations on H3K4, H3K9, H3K27, and H3K79 and upregulates several Hoxa genes by more than 10-fold.
“Transient knockdown of Fh in mouse livers significantly increased monomethylation on H3K4 (by 2.5-fold); dimethylation on H3K9 (by 4.2fold), H3K27 (by 4.3-fold), and H3K79 (by 5.2-fold); and trimethylation on H3K4 (by 2.8-fold).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Krivtsov et al. 2008
Not checked in the free run.
May combine two claims. The quote only partly states this claim.
Findingown dataTransient knockdown of Fh or Sdha in mouse liver increases fumarate or succinate, respectively, and elevates the succinate/α-KG ratio in Fh knockdown less than in Sdha knockdown.
“Transient knockdown of Fh or Sdha in mouse livers led to accumulation of intracellular fumarate or succinate, respectively, as determined by GC-MS”
- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · plain
“Notably, the succinate/a-KG ratio was also elevated in Fh knockdown liver cells, although less dramatically than Sdha knockdown.”
Quote in the paperSubstantial claim- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · plain
May combine two claims.
Findingown dataTumor-derived FH or SDH mutants lack function in fumarate or succinate metabolism.
“Tumor-derived FH or SDH mutants are not functional in fumarate or succinate metabolism.”
Quote in the paperSubstantial claimMay combine two claims.
Findingcitation5hmC is undetectable in most cultured cells but increases substantially when wild-type TET1 or TET2 catalytic domains are expressed.
“The 5hmC level in most cultured cells is undetectable, but is substantially increased in cells transiently expressing the wild-type catalytic domain of TET1 and TET2 proteins (TET1-CD and TET2-CD)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Tahiliani et al. 2009
Not checked in the free run.
- cites Ito et al. 2010
Not checked in the free run.
- cites He et al. 2011
Not checked in the free run.
Probably not a substantial claim: may not pass S1 (asserted), S4 (based). May combine two claims. The quote only partly states this claim.
Findingown dataWild-type FH or SDHA/B re-expression decreases histone methylation, HIF1α, and increases endostatin, while tumor-derived mutants do not show these changes.
“ectopic expression of wild-type FH or SDHA/B resulted in decreases of dimethylation on H3K9 (by 1.5fold) as well as monomethylation and trimethylation on H3K4 (by 2.5-fold and twofold, respectively), consistent with increased KDM activity”
- Also stated in: § Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases · plain
“these changes in genome-wide histone methylations were not observed in cells re-expressing tumor-derived FH or SDHA/B mutants”
Quote in the paperNot a substantial claim- Also stated in: § Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases · plain
May combine two claims.
Findingown dataCell-permeable fumarate and succinate increase HIF1α and decrease endostatin in HeLa and HEK293T cells.
“We found that cell-permeable fumarate and succinate increased HIF1a and decreased endostatin in both cell types”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFumarate and succinate inhibit HsKDM4A in a dose-dependent manner, with succinate more potent (IC50 0.8 mM vs 1.5 mM).
“Our results demonstrated that succinate (IC 50 = 0.8 mM) is more potent than fumarate (IC 50 = 1.5 mM) in inhibiting HsKDM4A”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataAdding 5 mM octyl-α-KG diminishes the effects of FH or SDHA/B knockdown on histone methylation, HIF1α, and endostatin in a dose-dependent manner.
“Addition of 5 mM octyl-a-KG diminished the effect of FH or SDHA/B suppression on increasing histone methylations, accumulating HIF1a, and decreasing endostatin”
- Also stated in: § Fumarate and succinate alter epigenetics · plain
“these effects of octyl-a-KG were in a dose-dependent manner”
Quote in the paperSubstantial claim- Also stated in: § Fumarate and succinate alter epigenetics · plain
May combine two claims.
PremisecitationFunctionally characterized FH or SDH mutations cause complete loss or reduced enzymatic activity, indicating that FH and SDH act as tumor suppressors.
“Thus far, all functionally characterized FH or SDH mutations result in either a complete loss or reduction of enzymatic activity (Tomlinson et al. 2002;Pollard et al. 2005), indicating that both FH and SDH function as tumor suppressors.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Tomlinson et al. 2002
Not checked in the free run.
- cites Pollard et al. 2005
Not checked in the free run.
May combine two claims.
PremisecitationIDH1 and IDH2 mutations simultaneously reduce α-KG production and increase 2-HG production.
“These mutations in IDH1/2 result in simultaneous loss and gain of activities in the production of a-ketoglutarate (a-KG) and 2-hydroxyglutarate (2-HG), respectively”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Dang et al. 2009
Not checked in the free run.
- cites Yan et al. 2009
Not checked in the free run.
- cites Zhao et al. 2009
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationJmjC domain histone demethylases and TET DNA hydroxylases are central to epigenetic control.
“Of the >60 estimated a-KGdependent dioxygenases in mammalian cells (Rose et al. 2011), the JmjC domain-containing histone demethylases (KDMs) and the TET (ten-eleven translocation) family of DNA hydroxylases play central roles in epigenetic control of genomic information.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rose et al. 2011
Not checked in the free run.
Classified as probably not a substantial claim.
PremisereasoningThe dioxygenase reaction uses α-KG as a cosubstrate and releases succinate and CO2.
“These enzymes require Fe(II) as a cofactor metal and a-KG as a cosubstrate to catalyze the reactions in which one oxygen atom from molecular oxygen (O 2 ) is attached to a hydroxyl group in the substrate (hydroxylation) while the other is taken up by a-KG, leading to the decarboxylation of a-KG and subsequent release of carbon dioxide (CO 2 ) and succinate.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTumor-derived FH and SDH mutations cause fumarate and succinate accumulation, which inhibits multiple α-KG-dependent dioxygenases and alters genome-wide histone and DNA methylation.
“Our study suggests that tumor-derived FH and SDH mutations accumulate fumarate and succinate, leading to enzymatic inhibition of multiple a-KG-dependent dioxygenases and consequent alterations of genome-wide histone and DNA methylation.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationTET enzymes oxidize 5mC in three steps to 5hmC, 5fC, and 5caC.
“the recently discovered TET family of DNA hydroxylases catalyzes a three-step iterative oxidation reaction: converting 5mC to 5-hydroxymethylcytosine (5hmC), then converting 5hmC to 5-formylcytosine (5fC), and finally converting 5fC to 5-carboxylcytosine (5caC)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Tahiliani et al. 2009
Not checked in the free run.
- cites Ito et al. 2010
Not checked in the free run.
- cites He et al. 2011
Not checked in the free run.
May combine two claims.
PremisecitationTumor-derived mutant IDH1 and IDH2 inhibit α-KG-dependent dioxygenases, and 2-HG competitively inhibits KDMs and TETs.
“We and others recently demonstrated that ectopic expression of tumor-derived mutated IDH1 and IDH2 inhibits the activity of a-KG-dependent dioxygenases and, more importantly, produces 2-HG, which acts as an antagonist of a-KG to competitively inhibit the activity of a-KG-dependent dioxygenases, including both KDMs and TETs”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Chowdhury et al. 2011
Not checked in the free run.
- cites Xu et al. 2011
Not checked in the free run.
May combine two claims.
PremisecitationFumarate and succinate accumulated in FH/SDH mutant cells inhibit PHDs, which hydroxylate HIF1α and promote its degradation.
“Studies into the mechanism behind how mutations in FH and SDH trigger elevated levels of HIF1a provided evidence that fumarate and succinate accumulated in cells with mutations in either FH or SDH inhibit prolyl hydroxylases (PHDs), which hydroxylates and promotes the degradation of HIF1a”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Epstein et al. 2001
Not checked in the free run.
- cites Yu et al. 2001
Not checked in the free run.
- cites Isaacs et al. 2005
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationTET catalytic activity depends on α-KG and is inhibited by 2-HG.
“Given the dependence of TET catalytic activity on a-KG and its inhibition by 2-HG (Xu et al. 2011)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xu et al. 2011
Not checked in the free run.
May combine two claims.
InterpretationreasoningAlterations of histone methylation likely have broad effects on gene expression, which may contribute to the tumor suppressor functions of FH and SDH.
“Moreover, alterations of histone methylation will likely have a broad impact on gene expression, which may also contribute to the tumor suppressor functions of FH and SDH.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataRe-expression of wild-type FH and SDH reduces fumarate and succinate and increases 5hmC by relieving TET inhibition.
“Re-expression of wild-type FH and SDH dramatically reduced fumarate and succinate, respectively, in the FH or SDH knockdown cells and thus increased 5hmC by relieving inhibition on TETs.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataDecreased FH and SDHA activity leads to fumarate and succinate accumulation, which inhibits α-KG-dependent dioxygenases and regulates target gene expression.
“Taken together, the above findings provide in vivo evidence supporting the notion that decreased activity of FH and SDHA leads to accumulation of fumarate and succinate, which inhibit a-KG-dependent dioxygenases and regulate target gene expression.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataKnockdown of FH and SDHA/B elevates fumarate and succinate, which compete with α-KG to inhibit TET-catalyzed 5mC hydroxylation.
“Taken together, these data indicate that knockdown of FH and SDHA/B leads to elevated levels of intracellular fumarate and succinate, respectively, which act as competitors of a-KG to inhibit TET-catalyzed hydroxylation of 5mC.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningTumor cells with FH or SDH mutations accumulate fumarate and succinate, which inhibit histone and DNA demethylation.
“These observations suggest that tumor cells containing FH or SDH mutations accumulate fumarate and succinate, which then inhibit histone and DNA demethylations.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTransient knockdown of Fh or Sdha inhibits TET activity without downregulating Tet gene transcription.
“Suppression of Fh or Sdha did not significantly affect the hepatic mRNA levels of Tet genes”
- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · hedged
“indicating that transient knockdown of Fh or Sdha would inhibit the activity of TETs by not down-regulating the transcription of TET genes.”
Quote in the paperSubstantial claim- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · hedged
May combine two claims.
Interpretationown dataFumarate and succinate act as α-KG antagonists to inhibit α-KG-dependent KDMs, with succinate being more potent than fumarate.
“Together, these results suggest that both fumarate and succinate act as antagonists of a-KG to inhibit a-KG- dependent KDMs, with succinate being more potent than fumarate.”
Quote in the paperSubstantial claim
The paper relies on this without support.
TET family enzymes function as tumor suppressors.
“Given the well-characterized tumor suppressor function of TET”
The paper relies on this without support.
Many missense mutations in FH or SDH have unknown functional consequences.
“There are also many missense mutations whose exact functional consequences have not been characterized.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Fumarate and succinate accumulation can inhibit some alpha-ketoglutarate-dependent dioxygenases, resulting in hypermethylation of DNA and histones in tumors with FH or SDH loss.
“Like D-2HG, fumarate and succinate accumulation can inhibit some αKG-dependent dioxygenases, resulting in hypermethylation of DNA and histones in tumors exhibiting loss of FH or SDH (Hoekstra et al., 2015; Letouze et al., 2013; Xiao et al., 2012).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Xiao et al., 2012
Increased levels of succinate and fumarate can inhibit Jumonji C-domain-containing histone demethylases and TET enzymes, driving a widespread hypermethylation phenotype that disrupts normal cell differentiation.
“Like 2HG accumulation, increased levels of succinate and fumarate can inhibit Jumonji C-domain–containing histone demethylases and TET enzymes, driving a widespread hypermethylation phenotype that disrupts normal cell differentiation (179, 180).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [180]
Tumors with SDH and FH loss share phenotypic features consistent with dioxygenase inhibition, including global increase in DNA methylation and elevated HIF1α.
“Tumors that exhibit SDH- and FH loss share a number of phenotypic features that are consistent with dioxygenase inhibition, among which is a characteristic global increase in DNA methylation (Killian et al., 2013; Letouze et al., 2013; Xiao et al., 2012), as well as elevated levels of HIF1α (Selak et al., 2005).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Xiao et al., 2012
Fumarate drives succination of Fe-S cluster biogenesis proteins, causing depletion of Fe-S clusters required for mitochondrial enzymes including complex I.
“Finally, it was shown that fumarate can drive succination of several members of the family of Iron Sulfur (Fe-S) cluster biogenesis proteins, causing a depletion of Fe-S clusters required for the activity of mitochondrial enzymes, including complex I88.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [88]
Succinate inhibits HIF-1α signaling through inhibition of PHD2 but can also impact the activity of numerous α-ketoglutarate-dependent dioxygenases.
“Succinate inhibits HIF-1␣ signaling through inhibition of PHD2 but can also impact the activity of numerous ␣-ketoglutarate-dependent dioxygenases (42,43).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [42]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
KDM7A substrate is described as both dimethylated and monomethylated
MinorThe assay description calls the H3K9 substrate dimethylated, but the peptide it says was used is monomethylated.
“To measure CeKDM7A demethylase activity toward dimethylated H3K9,”
“synthetic monomethylated peptide corresponding to monomethylated H3K9 (ARTKQTARK (me1)STGGKA) was used as substrate.”
Cites
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“Thus far, all functionally characterized FH or SDH mutations result in either a complete loss or reduction of enzymatic activity (Tomlinson et al. 2002; Pollard et al. 2005), indicating that both FH and SDH function as tumor suppressors.”
BackgroundInfluential<i>IDH1</i> and <i>IDH2</i> Mutations in Gliomas
Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808710 · Cited by 5,847 · see citing works
Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
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BackgroundSelf-citationCancer-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 · see citing works
Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
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“…mutated IDH1 and IDH2 inhibits the activity of a-KG-dependent dioxygenases and, more importantly, produces 2-HG, which acts as an antagonist of a-KG to competitively inhibit the activity of a-KG-dependent dioxygenases, including both KDMs and TETs (Chowdhury et al. 2011; Xu et al. 2011).”
BackgroundSelf-citationTet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA
He, Y., Li, B.-Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., et al. (2011) · Science · doi:10.1126/science.1210944 · Cited by 2,776 · see citing works
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BackgroundIdentification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma
Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., Pan, F., Pelloski, C. E., Sulman, E. P., Bhat, K. P., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.03.017 · Cited by 2,337 · cited 2× · see citing works
“These findings provide a biochemical basis for the hypermethylation observed in human glioma with IDH1 mutation (Noushmehr et al. 2010) and the mutually exclusive manner of IDH1/2 and TET2 gene mutations in AML (Lorsbach et al.”
BackgroundRecurring mutations found by sequencing an acute myeloid leukemia genome
Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903840 · Cited by 2,219 · cited 1× · see citing works
“…IDH1 and IDH2 are frequently mutated in >75% of glioma (Parsons et al. 2008), ;20% of acute myeloid leukaemia (AML) (Mardis et al. 2009), and several additional tumors at different frequencies (Hemerly et al. 2010; Murugan et al. 2010; Amary et al. 2011; Damato et al. 2012; Oermann et al. 2012).”
BackgroundHistone demethylation by a family of JmjC domain-containing proteins
Tsukada, Y.-I., Fang, J., Erdjument‐Bromage, H., Warren, M., Borchers, C. H., Tempst, P., & Zhang, Y. (2005) · Nature · doi:10.1038/nature04433 · Cited by 2,171 · cited 2× · see citing works
“While the KDMs catalyze the typical hydroxylation on the methyl group on the lysine residue (Tsukada et al. 2006), the recently discovered TET family of DNA hydroxylases catalyzes a three-step iterative oxidation reaction: converting 5mC to 5-hydroxymethylcytosine (5hmC), then converting 5hmC to…”
BackgroundSuccinate 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 · see citing works
Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli
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Mutations in <i>SDHD</i> , a Mitochondrial Complex II Gene, in Hereditary Paraganglioma
Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., Mey, A. V. D., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., et al. (2000) · Science · doi:10.1126/science.287.5454.848 · Cited by 1,638 · see citing works
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“Thus far, all functionally characterized FH or SDH mutations result in either a complete loss or reduction of enzymatic activity (Tomlinson et al. 2002; Pollard et al. 2005), indicating that both FH and SDH function as tumor suppressors.”
BackgroundMolecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution
Taguchi, K., Motohashi, H., & Yamamoto, M. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2010.01473.x · Cited by 1,478 · cited 1× · see citing works
“Moreover, KEAP1 and NRF2 have been implicated in tumor development (Taguchi et al. 2011), although their contributions to oncogenesis in FH mutant cancer still require further exploration.”
BackgroundGlioma-Derived Mutations in <i>IDH1</i> 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 · cited 2× · see citing works
“…and gain of activities in the production of a-ketoglutarate (a-KG) and 2-hydroxyglutarate (2-HG), respectively (Dang et al. 2009; Yan et al. 2009; Zhao et al. 2009). a-KG plays critical roles in four different metabolic and cellular pathways: as an intermediate in the Krebs cycle for energy…”
BackgroundSelf-citationAstuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Sköldberg, F., Husebye, E. S., Eng, C., & Maher, E. R. (2001) · The American Journal of Human Genetics · doi:10.1086/321282 · Cited by 1,087 · cited 1× · see citing works
“…SDHA, SDHB, SDHC, SDHD, and SDHAF2), encoding for the subunits of two different Krebs cycle enzymes (FH and SDH), are mutated both germinally and somatically in a number of human cancers (Baysal et al. 2000; Astuti et al. 2001; Hao et al. 2009; Kaelin 2009; Bayley et al. 2010; Oermann et al. 2012).”
BackgroundThe oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases
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., et al. (2011) · The EMBO Reports · doi:10.1038/embor.2011.43 · Cited by 1,035 · see citing works
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“…IDH1 and IDH2 are frequently mutated in >75% of glioma (Parsons et al. 2008), ;20% of acute myeloid leukaemia (AML) (Mardis et al. 2009), and several additional tumors at different frequencies (Hemerly et al. 2010; Murugan et al. 2010; Amary et al. 2011; Damato et al. 2012; Oermann et al. 2012).”
BackgroundIsaacs, J. S., Jung, Y. J., Mole, D. R., Lee, S., Torres-Cabala, C., Chung, Y.-L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.017 · Cited by 958 · see citing works
Fe(II)/α-Ketoglutarate-Dependent Hydroxylases and Related Enzymes
Hausinger, R. P. (2004) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409230490440541 · Cited by 937 · cited 15× · see citing works
“The DNA amount used for dot blot analysis was determined by methylene blue staining (Supplemental Fig.”
BackgroundInfluentialPollard, P. J., Brière, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi227 · Cited by 865 · cited 3× · see citing works
“Thus far, all functionally characterized FH or SDH mutations result in either a complete loss or reduction of enzymatic activity (Tomlinson et al. 2002; Pollard et al. 2005), indicating that both FH and SDH function as tumor suppressors.”
BackgroundInfluentialHIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation
Yu, F., White, S. B., Zhao, Q., & Lee, F. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181341498 · Cited by 796 · cited 1× · see citing works
“…elevated levels of HIF1a provided evidence that fumarate and succinate accumulated in cells with mutations in either FH or SDH inhibit prolyl hydroxylases (PHDs), which hydroxylates and promotes the degradation of HIF1a (Epstein et al. 2001; Yu et al. 2001; Isaacs et al. 2005; Selak et al. 2005).”
BackgroundHao, H.-X., Khalimonchuk, O., Schraders, M., Dephoure, N., Bayley, J.-P., Kunst, H., Devilee, P., Cremers, C. W. R. J., Schiffman, J. D., Bentz, B. G., et al. (2009) · Science · doi:10.1126/science.1175689 · Cited by 702 · see citing works
Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer
King, A., Selak, M. A., & Gottlieb, E. (2006) · Oncogene · doi:10.1038/sj.onc.1209594 · Cited by 672 · see citing works
Adam, J., Hatipoglu, E., O'Flaherty, L., Ternette, N., Sahgal, N., Lockstone, H., Baban, D., Nye, E., Stamp, G. W., Wolhuter, K., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.09.006 · Cited by 585 · cited 2× · see citing works
“KEAP1 is the principal regulator of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) via controlling its ubiquitylation and degradation, thereby activating the antioxidant pathway (Adam et al. 2011; Ooi et al. 2011).”
BackgroundH3K79 methylation profiles define murine and human MLL-AF4 leukemias
Krivtsov, A., Feng, Z.-H., Lemieux, M., Faber, J., Vempati, S., Sinha, A., Xia, X.-B., Jesneck, J., Bracken, A., Silverman, L., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.10.001 · Cited by 573 · cited 2× · see citing works
“To further substantiate the above results, we determined mRNA expression of Hoxa genes whose up-regulation is associated with increased H3K79 dimethylation in MLL rearranged mouse leukemia and human AML patients (Krivtsov et al. 2008).”
ResultExpanding chemical biology of 2-oxoglutarate oxygenases
Loenarz, C., & Schofield, C. J. (2008) · Nature Chemical Biology · doi:10.1038/nchembio0308-152 · Cited by 498 · see citing works
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“The NADP+-dependent IDH genes IDH1 and IDH2 are frequently mutated in >75% of glioma (Parsons et al. 2008), ;20% of acute myeloid leukaemia (AML) (Mardis et al. 2009), and several additional tumors at different frequencies (Hemerly et al. 2010; Murugan et al. 2010; Amary et al. 2011; Damato et al. 2012; Oermann et al.…”
BackgroundInfluentialOoi, A., Wong, J.-C., Petillo, D., Roossien, D., Perrier-Trudova, V., Whitten, D., Min, B. W. H., Tan, M.-H., Zhang, Z., Yang, X. J., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.08.024 · Cited by 401 · see citing works
Inhibition of 2-oxoglutarate dependent oxygenases
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“…FH and SDH mutants inhibit a-KG-dependent dioxygenases Most tumor-derived mutations targeting FH or SDH genes cause obvious loss of function such as truncation or frameshift (Alam et al. 2005; Bayley et al. 2008; Bardella et al. 2011), which would eliminate the activity of FH or SDH enzymes.”
BackgroundMacKenzie, E. D., Selak, M. A., Tennant, D. A., Payne, L. J., Crosby, S., Frederiksen, C. M., Watson, D. G., & Gottlieb, E. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01927-06 · Cited by 359 · cited 4× · see citing works
“The NADP+-dependent IDH genes IDH1 and IDH2 are frequently mutated in >75% of glioma (Parsons et al. 2008), ;20% of acute myeloid leukaemia (AML) (Mardis et al. 2009), and several additional tumors at different frequencies (Hemerly et al. 2010; Murugan et al. 2010; Amary et al. 2011; Damato et al. 2012; Oermann et al.…”
BackgroundInfluentialSDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma
Bayley, J., Kunst, H. P. M., Cascón, A., Sampietro, M. L., Gaal, J., Korpershoek, E., Hinojar‐Gutiérrez, A., Timmers, H. J. L. M., Hoefsloot, L. H., Hermsen, M. A. J. A., et al. (2010) · The Lancet Oncology · doi:10.1016/s1470-2045(10)70007-3 · Cited by 275 · see citing works
Collagen Proline Hydroxylase in Wound Healing, Granuloma Formation, Scurvy, and Growth
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“These findings provide a biochemical basis for the hypermethylation observed in human glioma with IDH1 mutation (Noushmehr et al. 2010) and the mutually exclusive manner of IDH1/2 and TET2 gene mutations in AML (Lorsbach et al. 2003; Figueroa et al. 2010).”
BackgroundThe role of mitochondria in pharmacotoxicology: A reevaluation of an old, newly emerging topic
Scatena, R., Bottoni, P., Botta, G., Martorana, G. E., & Giardina, B. (2007) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00314.2006 · Cited by 163 · cited 2× · see citing works
“The tumor suppressor roles of FH and SDH mutations have been proposed to (1) abrogate the mitochondrial function to trigger apoptosis (Scatena et al. 2007), (2) generate harmful reactive oxygen species (ROS) that induce DNA damage and genomic instability (Kaelin 2009), and (3) provoke accumulation…”
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“…FH and SDH mutants inhibit a-KG-dependent dioxygenases Most tumor-derived mutations targeting FH or SDH genes cause obvious loss of function such as truncation or frameshift (Alam et al. 2005; Bayley et al. 2008; Bardella et al. 2011), which would eliminate the activity of FH or SDH enzymes.”
BackgroundMurugan, A. K., Bojdani, E., & Xing, M. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.02.095 · Cited by 132 · cited 5× · see citing works
“TET-catalyzed 5hmC production in cultured cells In addition to KDMs, PHDs and C-P4Hs, another class of Fe(II)- and a-KG-dependent dioxygenases is the TET family of DNA hydroxylases.”
BackgroundInfluentialAlterations of metabolic genes and metabolites in cancer
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“KEAP1 is the principal regulator of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) via controlling its ubiquitylation and degradation, thereby activating the antioxidant pathway (Adam et al. 2011; Ooi et al. 2011).”
BackgroundSelf-citationIdentification of several novel non-p.R132 IDH1 variants in thyroid carcinomas
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“…FH and SDH mutants inhibit a-KG-dependent dioxygenases Most tumor-derived mutations targeting FH or SDH genes cause obvious loss of function such as truncation or frameshift (Alam et al. 2005; Bayley et al. 2008; Bardella et al. 2011), which would eliminate the activity of FH or SDH enzymes.”
BackgroundDamato, S., Alorjani, M. S., Bonar, F., McCarthy, S. W., Cannon, S. R., O’Donnell, P., Tirabosco, R., Amary, F. M., & Flanagan, A. M. (2011) · Histopathology · doi:10.1111/j.1365-2559.2011.04010.x · Cited by 69 · cited 2× · see citing works
“…IDH1 and IDH2 are frequently mutated in >75% of glioma (Parsons et al. 2008), ;20% of acute myeloid leukaemia (AML) (Mardis et al. 2009), and several additional tumors at different frequencies (Hemerly et al. 2010; Murugan et al. 2010; Amary et al. 2011; Damato et al. 2012; Oermann et al. 2012).”
BackgroundSDH5 mutations and familial paraganglioma: somewhere Warburg is smiling
Kaelin, W. G. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.08.013 · Cited by 67 · see citing works
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Self-citationLessons from the deep study of rare tumours
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The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926 · see citing works
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“Like D2HG, evidence indicates that succinate and fumarate interfere with dioxygenase activity, supporting the notion that a general property of oncometabolites is the ability to regulate epigenetics (52, 53).”
BackgroundMitochondrial TCA cycle metabolites control physiology and disease
Martínez-Reyes, I., & Chandel, N. S. (2020) · Nature Communications · doi:10.1038/s41467-019-13668-3 · Cited by 2,813 · see citing works
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Mills, E. L., Kelly, B., Logan, A., Costa, A. S. H., Varma, M., Bryant, C. E., Tourlomousis, P., Däbritz, J. H. M., Gottlieb, E., Latorre, I., et al. (2016) · Cell · doi:10.1016/j.cell.2016.08.064 · Cited by 2,291 · see citing works
“TNF-a production, or this may be a result of epigenetic alterations of the TNF-a gene, which have been reported elsewhere (Sullivan et al., 2007; Xiao et al., 2012).”
BackgroundThe diverse roles of DNA methylation in mammalian development and disease
Greenberg, M., & Bourc’his, D. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0159-6 · Cited by 2,160 · see citing works
The multifaceted contributions of mitochondria to cellular metabolism
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“Interestingly, other Krebs cycle control genes, when mutated in certain tumor types, can also result in decreased a-ketoglutarate levels and similar chromatin and DNA methylation abnormalities (Xiao et al. 2012; Mason and Hornick 2013).”
BackgroundComprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma
The Cancer Genome Atlas Research Network (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1505917 · Cited by 1,336 · see citing works
Mitochondrial metabolism and cancer
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“All these oncometabolites share the capacity to inhibit α-ketoglutarate (α-KG)-dependent enzymes that control gene expression at the epigenetic level, such as Jumonji domain (JMJ) histone lysine demethylases as well as ten-eleven translocation (TET) dioxygenases [43, 44], resulting in the expression of a potentially o…”
BackgroundRole of TET enzymes in DNA methylation, development, and cancer
Rasmussen, K. D., & Helin, K. (2016) · Genes & Development · doi:10.1101/gad.276568.115 · Cited by 1,040 · see citing works
Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions
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“Similarly, inactivation mutations in SDH and FH, which have been identified in a subset of cancers, lead tomarked accumulation of succinate and fumarate, both of which can inhibit a-KG-dependent dioxygenases (Xiao et al., 2012).”
Identification of bioactive metabolites using activity metabolomics
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Targeting Metabolism for Cancer Therapy
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“Familial cancer syndromes caused by fumarate hydratase (FH) or succinate dehydrogenase (SDH) deletion suggest that these TCA enzymes can behave as classical tumor suppressors.”
BackgroundInfluentialCancer Cell Metabolism: One Hallmark, Many Faces
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“Interestingly, recent evidence has further suggested that the accumulation of both succinate and fumarate that arise in SDH- and FH-deficient tumors respectively (as described above), may also inhibit various αKG-dependent dioxygenases, resulting in analogous deregulation of epigenetic modifications (96).”
BackgroundHow cancer metabolism is tuned for proliferation and vulnerable to disruption
Schulze, A., & Harris, A. L. (2012) · Nature · doi:10.1038/nature11706 · Cited by 927 · see citing works
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“KDMs of the JmjC and JmjD family need a-ketoglutarate as a cofactor for the demethylation process (Lu et al., 2012), whereas metabolites with a similar molecular structure, such as fumarate, can act as antagonizing factors (Lu et al., 2012; Xiao et al., 2012), thereby inhibiting demethylation.”
BackgroundInfluence of Metabolism on Epigenetics and Disease
Kaelin, W. G., & McKnight, S. L. (2013) · Cell · doi:10.1016/j.cell.2013.03.004 · Cited by 920 · see citing works
“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…”
Epigenetic modulators, modifiers and mediators in cancer aetiology and progression
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Ten principles of heterochromatin formation and function
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Glutaminolysis: A Hallmark of Cancer Metabolism
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“The loss of succinate dehydrogenase or fumarate hydratase in tumors leads to altered ratios of α-ketoglutarate to succinate that can affect genome-wide methylation (6, 120, 121).”
BackgroundMetabolic reprogramming and epigenetic modifications on the path to cancer
Sun, L., Zhang, H., & Gao, P. (2021) · Protein & Cell · doi:10.1007/s13238-021-00846-7 · Cited by 796 · see citing works
“These epigenetic alterations induced by FH or SDH loss contribute to tumorigenesis (Xiao et al., 2012).”
BackgroundMitochondrial Metabolism as a Target for Cancer Therapy
Vasan, K., Werner, M., & Chandel, N. S. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.019 · Cited by 746 · see citing works
SDH mutations establish a hypermethylator phenotype in paraganglioma
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“Fumarate, like succinate, is a competitive inhibitor of 2-OG-dependent dioxygenases (Xiao et al., 2012), so these findings strongly suggest that FH inactivation causes PGL/PCC by establishing a hypermethylator phenotype.”
BackgroundImmunometabolic Pathways in BCG-Induced Trained Immunity
Arts, R. J. W., Carvalho, A., Rocca, C. L., Palma, C., Rodrigues, F. J. S., Silvestre, R., Kleinnijenhuis, J., Lachmandas, E., Gonçalves, L. G., Belinha, A., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.11.011 · Cited by 677 · see citing works
“Metabolites with a similar molecular structure—such as fumarate, succinate, or 2-hydroxyglutarate— can, in turn, serve as antagonizing factors (Lu et al., 2012; Xiao et al., 2012), thereby inhibiting the demethylation process.”
BackgroundHow the Warburg effect supports aggressiveness and drug resistance of cancer cells?
Icard, P., Shulman, S. D., Farhat, D., Steyaert, J., Alifano, M., & Lincet, H. (2018) · Drug Resistance Updates · doi:10.1016/j.drup.2018.03.001 · Cited by 648 · see citing works
Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine
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Amino Assets: How Amino Acids Support Immunity
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Tumour hypoxia causes DNA hypermethylation by reducing TET activity
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Mechanisms and Implications of Metabolic Heterogeneity in Cancer
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Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation
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“overexpression also result in methylation changes in cancer cells (Killian et al., 2013; Letouze et al., 2013; Ulanovskaya et al., 2013; Xiao et al., 2012).”
BackgroundSuccinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis.
Tretter, L., Patócs, A., & Chinopoulos, C. (2016) · Biochimica et Biophysica Acta · doi:10.1016/j.bbabio.2016.03.012 · Cited by 502 · see citing works
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Epigenetic Therapies for Cancer
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Regulation and function of the mammalian tricarboxylic acid cycle
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“Indeed, succinate can inhibit various other -ketoglutarate-dependent dioxygenases to impact diverse cellular processes (42, 43).”
BackgroundMitochondrial Dysfunction in Cancer
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“Thus, the downstream consequences of increased fumarate, succinate, or 2HG include the accumulation of HIF-α and increased HIF target gene expression (235, 238), defects in collagen maturation (239), as well as hypermethylation and altered histone code due to disruption of epigenetic control of gene expression (236, 2…”
BackgroundMitochondrial complex III is essential for suppressive function of regulatory T cells
Weinberg, S. E., Singer, B. D., Steinert, E. M., Martinez, C. A., Mehta, M., Martínez‐Reyes, I., Gao, P., Helmin, K. A., Abdala‐Valencia, H., Sena, L. A., et al. (2019) · Nature · doi:10.1038/s41586-018-0846-z · Cited by 496 · see citing works
KDM4/JMJD2 Histone Demethylases: Epigenetic Regulators in Cancer Cells
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“1C), leading to accumulation of succinate that is an end-product inhibitor of JMJD proteins, including KDM4A and KDM4D (70, 71).”
BackgroundImmunometabolism: Cellular Metabolism Turns Immune Regulator
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“Indeed, succinate can inhibit other -ketoglutarate-dependent enzymes that can impact upon immune cells due their roles in controlling cellular epigenetics, namely TET2 DNA hydroxylates and Jumonji C (JmjC) domain-containing histone demethylases (discussed further below) (84, 85).”
Krebs cycle Reborn in macrophage immunometabolism
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“In addition to the PHDs, α-ketoglutarate is an important cofactor for the α-KGDD family of Jumonji-C-domain-containing histone demethylases ( JMJDs), involved in histone demethylation, and the ten eleven translocation (TET) family of 5mC hydroxylases, which play a role in DNA demethylation (64).”
BackgroundMitochondrial dysfunction and mitochondrial dynamics-The cancer connection
Srinivasan, S., Guha, M., Kashina, A., & Avadhani, N. G. (2017) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2017.01.004 · Cited by 435 · see citing works
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Self-citationThe Intersection of Epigenetics and Metabolism in Trained Immunity
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Coupling Krebs cycle metabolites to signalling in immunity and cancer
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Altered metabolite levels in cancer: implications for tumour biology and cancer therapy
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Methionine is a metabolic dependency of tumor-initiating cells
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Self-citationGermline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas
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Energy metabolism in health and diseases
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Mitochondria and Epigenetics – Crosstalk in Homeostasis and Stress
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Understanding metabolic regulation and its influence on cell physiology
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“Succinate and fumarate abundances increase with oncogenic loss-of-function mutations in the TCA cycle enzymes SDH and FH, and both metabolites can affect dioxygenase activity (Xiao et al., 2012).”
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Nutrient Sensing, Metabolism, and Cell Growth Control
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“For example, high concentration of succinate and fumarate can inhibit the activity of TET2 and KDM4A, a JmjC family histone demethylase (Xiao et al., 2012).”
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Mechanism and Function of Oxidative Reversal of DNA and RNA Methylation
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“Both function as competitive inhibitors of Fe(II)/αKG-dependent dioxygenases and accumulate in a subset of human cancers with inactivation mutations of fumarate hydratase (FH ) and succinate dehydrogenase (SDH ), respectively (85).”
Trained Immunity: Reprogramming Innate Immunity in Health and Disease
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Metabolic Regulation of Histone Post-Translational Modifications
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“These mutations result in decreased or complete loss of enzymatic activity, causing robust accumulation of succinate or fumurate (86).”
BackgroundMetabolic signatures of cancer cells and stem cells
Intlekofer, A. M., & Finley, L. W. S. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0032-0 · Cited by 322 · see citing works
Fumarate induces vesicular release of mtDNA to drive innate immunity
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The Metabolic Basis of Kidney Cancer
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Rewiring urea cycle metabolism in cancer to support anabolism
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Dysregulated metabolism contributes to oncogenesis
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“More recently, it has been identified that succinate and fumarate also inhibit histone demethylases and TET proteins [220].”
Oncometabolites suppress DNA repair by disrupting local chromatin signalling
Sulkowski, P. L., Oeck, S., Dow, J., Economos, N. G., Mirfakhraie, L., Liu, Y., Noronha, K. J., Bao, X., Li, J., Shuch, B. M., et al. (2020) · Nature · doi:10.1038/s41586-020-2363-0 · Cited by 311 · see citing works
Self-citationThe mitochondrial respiratory chain is essential for haematopoietic stem cell function
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“The TCA cycle metabolites succinate and fumarate, as well as the oncometabolite 2-hydroxyglutrate (2HG), are antagonists of α -KG, competitively inhibiting the activity of α -KG-dependent dioxygenases, including KDMs and TETs 28, 29 .”
Role of mitochondrial dysfunction in cancer progression
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“Moreover, the accumulation of succinate was found to result in epigenetic changes in gene expression by the inhibition of a-ketoglutarate-dependent histone and DNA demethylases.(68,84,85)”
BackgroundThe Proto-oncometabolite Fumarate Binds Glutathione to Amplify ROS-Dependent Signaling
Sullivan, L. B., Martinez-Garcia, E., Nguyen, H., Mullen, A. R., Dufour, E., Sudarshan, S., Licht, J. D., Deberardinis, R. J., & Chandel, N. S. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.05.003 · Cited by 304 · see citing works
“A recent study demonstrated that RNAi of FH in HEK293 cells also increases hypermethylation of histones (Xiao et al., 2012).”
Backgroundα-Ketoglutarate links p53 to cell fate during tumour suppression
Morris, J. P., Yashinskie, J. J., Koche, R., Chandwani, R., Tian, S., Chen, C.-C., Baslan, T., Marinkovic, Z. S., Sánchez-Rivera, F. J., Leach, S. D., et al. (2019) · Nature · doi:10.1038/s41586-019-1577-5 · Cited by 296 · see citing works
Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes
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“8 mM, respectively, and induce genome-wide histone methylation in cellulo, likely adding to the epigenetic regulation that occurs via these metabolites (30).”
BackgroundMetabolic control of methylation and acetylation
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Mitochondrial DNA variation and cancer
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Mitochondrial complex ii: At the crossroads
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<scp>l</scp> -2-Hydroxyglutarate: An Epigenetic Modifier and Putative Oncometabolite in Renal Cancer
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“Multiple studies have demonstrated that fumarate, succinate, and 2HG can inhibit TET enzymatic activity(11, 27, 28).”
Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis
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“Considering this limitation, the RNA interference-mediated silencing of SDH subunits in cancer cell allowed a partial understanding of cellular effects of mitochondrial complex II deficiency 14, 17, 18 .”
α-Ketoglutarate Accelerates the Initial Differentiation of Primed Human Pluripotent Stem Cells
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Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription
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TET (Ten-eleven translocation) family proteins: structure, biological functions and applications
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“In addition to 2HG, succinate and fumarate were also identified to act as α-KG antagonists, which inhibited TET2 dioxygenase activity.(233) Recently, Chen et al.”
BackgroundThe functional roles of TCA cycle metabolites in cancer
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Marked for death: Targeting epigenetic changes in cancer
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Epigenetics and Trained Immunity
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“Importantly, TCA cycle intermediates succinate and fumarate can inhibit certain demethylation reactions (143).”
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Connections between TET proteins and aberrant DNA modification in cancer
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Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs
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Interplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches
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Cancer metabolism and mitochondria: Finding novel mechanisms to fight tumours
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Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations
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Self-citationMetabolic adaptation in hypoxia and cancer
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“Elevated levels of succinate caused by SDH loss-of-function are associated with impaired JmjC and TET activity, leading to dysregulation of proliferation and migration genes [72], loss of the Electron transport chain complex II [15, 73], and increased ROS production [69].”
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Oxidative Stress Signaling to Chromatin in Health and Disease
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Defects in mitochondrial metabolism and cancer
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“More recently, succinate was found to be a prototypical ‘epigenetic hacker’ [45], capable of inhibiting both DNA [46,47] and histone demethylases [48], leading to epigenetic changes that overlap with those observed in mutant IDH cancers [49].”
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Self-citation
- Authors
- Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., Zhao, S., Ye, D., Xiong, Y., & Guan, K.-L.
- Affiliations
- Fudan University (CN)
- Shanghai Medical College of Fudan University (CN)
- Chinese Academy of Sciences (CN)
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-06-07
- Volume
- 26
- Issue
- 12
- Pages
- 1326-1338
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3387660
- OpenAlex
- W2104852749
- Semantic Scholar
- 0692bd51f83e69f21dab4f3e869a55299d72df6b
- Cited by
- 1,188
- References
- 50
- Citations by year
- 2026: 141 · 2025: 96 · 2024: 85 · 2023: 100 · 2022: 99 · 2021: 96 · 2020: 105 · 2019: 91 · 2018: 70 · 2017: 84 · 2016: 74 · 2015: 54 · 2014: 50 · 2013: 33 · 2012: 9
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- James S. McDonnell Foundation
- Samuel Waxman Cancer Research Foundation
- National Natural Science Foundation of China (2012CB910101, 2012CB910300, 30600112, 31071192, 81120108016, 30871255)
- National Institutes of Health
- Shanghai Leading Academic Discipline Project
- National Cancer Institute (F31CA260794)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- fumarate hydratase, succinate dehydrogenase, fumarate, succinic acid, alpha-ketoglutarate-dependent dioxygenase, histone demethylase, DNA demethylase, prolyl hydroxylase, collagen prolyl 4-hydroxylase, competitive inhibition, tumor suppressor mutations, epigenetic modifications, DNA methylation, histone methylation, TCA cycle, carcinogenesis
- MeSH terms
- Animals, Cells, Cultured, Fumarate Hydratase, Fumarates, Gene Expression Regulation, Humans, Ketoglutaric Acids, Models, Biological, Mutation, Succinate Dehydrogenase, Genome, Human, DNA Methylation, Succinic Acid, Tumor Suppressor Proteins, Endostatins, Dioxygenases, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Biocatalysis, Gene Knockdown Techniques, Histone Demethylases, HEK293 Cells
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