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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.
Overview
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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.
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43 Own result · 20 Own interpretation · 14 Not checked yet · 3 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ectopic expression of tumor-derived FH and SDH mutants inhibits histone demethylation and hydroxylation of 5mC.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Fumarate and succinate inhibit the demethylase activity of human KDM4A (HsKDM4A) toward trimethylated H3K36, determined by mass spectrometry (MS) assay as in B.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Statistical analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Knocking down FH or SDH reduces the TET-catalyzed 5hmC production in cultured cells.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Statistical analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Fumarate and succinate increase genome-wide histone methylations, accumulate HIF1a, and reduce endostatin in cultured cells.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Statistical analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Statistical analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Statistical analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Fumarate and succinate inhibit the activity of a-KG-dependent KDMs in vitro.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Statistical analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Succinate is more potent to inhibit HsKDM4A than fumarate.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Statistical analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 30
- The quote only partly states this claim. 6
- Probably not a substantial claim. 6
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Knockdown of FH and SDH results in elevated intracellular levels of fumarate and succinate, respectively”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Suppression of FH or SDH expression reduces TET-catalyzed 5hmC production in cultured cells
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Suppression of FH or SDH expression reduces TET-catalyzed 5hmC production in cultured cells · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Both fumarate and succinate increase genome-wide histone methylations, accumulate HIF1a, and reduce endostatin in cultured cells
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
- Also stated in: § Both fumarate and succinate increase genome-wide histone methylations, accumulate HIF1a, and reduce endostatin in cultured cells · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Both fumarate and succinate inhibit the activity of a-KG-dependent KDMs in vitro
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
- Also stated in: § Both fumarate and succinate inhibit the activity of a-KG-dependent KDMs in vitro · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cell-permeable fumarate and succinate increased H3K4 monomethylation (by fourfold), H3K27 and H3K79 dimethylation (by fourfold and threefold, respectively), and H3K4 trimethylation (by twofold)”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Both fumarate and succinate increase genome-wide histone methylations, accumulate HIF1a, and reduce endostatin in cultured cells
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Fumarate and succinate alter epigenetics
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Fumarate and succinate alter epigenetics · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases · plain
In the paper
“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).”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo
What the sources say
- Not checked yetcites Krivtsov et al. 2008
plaindirect- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true. The paper may give no reason why it holds. It may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one. The quote only partly states this claim.
- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tumor-derived FH or SDH mutants are not functional in fumarate or succinate metabolism.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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)”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Suppression of FH or SDH expression reduces TET-catalyzed 5hmC production in cultured cells
What the sources say
- Not checked yetcites Tahiliani et al. 2009
- Not checked yetcites Ito et al. 2010
- Not checked yetcites He et al. 2011
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases
plaindirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper may give no reason why it holds. It may state two separate claims as one. The quote only partly states this claim.
- Also stated in: § Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that cell-permeable fumarate and succinate increased HIF1a and decreased endostatin in both cell types”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Both fumarate and succinate increase genome-wide histone methylations, accumulate HIF1a, and reduce endostatin in cultured cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results demonstrated that succinate (IC 50 = 0.8 mM) is more potent than fumarate (IC 50 = 1.5 mM) in inhibiting HsKDM4A”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Both fumarate and succinate inhibit the activity of a-KG-dependent KDMs in vitro
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Fumarate and succinate alter epigenetics
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
- Also stated in: § Fumarate and succinate alter epigenetics · plain
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
What the sources say
- Not checked yetcites Tomlinson et al. 2002
- Not checked yetcites Pollard et al. 2005
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
What the sources say
- Not checked yetcites Dang et al. 2009
- Not checked yetcites Yan et al. 2009
- Not checked yetcites Zhao et al. 2009
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
What the sources say
- Not checked yetcites Rose et al. 2011
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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)”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
What the sources say
- Not checked yetcites Tahiliani et al. 2009
- Not checked yetcites Ito et al. 2010
- Not checked yetcites He et al. 2011
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
What the sources say
- Not checked yetcites Chowdhury et al. 2011
- Not checked yetcites Xu et al. 2011
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Abstract
What the sources say
- Not checked yetcites Epstein et al. 2001
- Not checked yetcites Yu et al. 2001
- Not checked yetcites Isaacs et al. 2005
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Given the dependence of TET catalytic activity on a-KG and its inhibition by 2-HG (Xu et al. 2011)”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Suppression of FH or SDH expression reduces TET-catalyzed 5hmC production in cultured cells
What the sources say
- Not checked yetcites Xu et al. 2011
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Tumor-derived FH and SDH mutants inhibit a-KG-dependent dioxygenases
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Suppression of FH or SDH expression reduces TET-catalyzed 5hmC production in cultured cells
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These observations suggest that tumor cells containing FH or SDH mutations accumulate fumarate and succinate, which then inhibit histone and DNA demethylations.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Knocking down Fh or Sdha inhibits multiple a-KG-dependent dioxygenases and regulates target gene expression in vivo · hedged
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Both fumarate and succinate inhibit the activity of a-KG-dependent KDMs in vitro
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Enzyme activity assay
“To measure CeKDM7A demethylase activity toward dimethylated H3K9,”
§ Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors > Enzyme activity assay
“synthetic monomethylated peptide corresponding to monomethylated H3K9 (ARTKQTARK (me1)STGGKA) was used as substrate.”
Citations
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Self-citation
Metadata
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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