Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition

doi:10.1038/nature19353

. 2016 Aug 31;537(7621):544-547.

doi: 10.1038/nature19353.

Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition

Marco Sciacovelli¹, Emanuel Gonçalves², Timothy Isaac Johnson¹, Vincent Roberto Zecchini¹, Ana Sofia Henriques da Costa¹, Edoardo Gaude¹, Alizee Vercauteren Drubbel¹, Sebastian Julian Theobald¹, Sandra Riekje Abbo¹, Maxine Gia Binh Tran³, Vinothini Rajeeve⁴, Simone Cardaci⁵, Sarah Foster⁶, Haiyang Yun⁷, Pedro Cutillas⁴, Anne Warren⁸, Vincent Gnanapragasam⁹, Eyal Gottlieb⁵, Kristian Franze⁶, Brian Huntly⁷, Eamonn Richard Maher^{10

11}, Patrick Henry Maxwell¹², Julio Saez-Rodriguez^{2

13}, Christian Frezza¹

Affiliations

¹ Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
² European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute (EBI), Cambridge CB10 1SD, UK.
³ Department of Oncology, Uro-Oncology Research Group, University of Cambridge, Cambridge CB2 0Ql, UK.
⁴ Integrative Cell Signalling and Proteomics, Centre for Haemato-Oncology, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
⁵ Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
⁶ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
⁷ Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke's Hospital, and Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK.
⁸ Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK.
⁹ Academic Urology Group, Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK.
¹⁰ Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.
¹¹ NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
¹² Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
¹³ RWTH Aachen University, Faculty of Medicine, Joint Research Center for Computational Biomedicine, Aachen 52074, Germany.

PMID: 27580029
PMCID: PMC5136292
DOI: 10.1038/nature19353

Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition

Marco Sciacovelli et al. Nature. 2016.

. 2016 Aug 31;537(7621):544-547.

doi: 10.1038/nature19353.

Authors

Affiliations

¹ Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
² European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute (EBI), Cambridge CB10 1SD, UK.
³ Department of Oncology, Uro-Oncology Research Group, University of Cambridge, Cambridge CB2 0Ql, UK.
⁴ Integrative Cell Signalling and Proteomics, Centre for Haemato-Oncology, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
⁵ Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
⁶ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
⁷ Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke's Hospital, and Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK.
⁸ Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK.
⁹ Academic Urology Group, Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK.
¹⁰ Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.
¹¹ NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
¹² Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
¹³ RWTH Aachen University, Faculty of Medicine, Joint Research Center for Computational Biomedicine, Aachen 52074, Germany.

PMID: 27580029
PMCID: PMC5136292
DOI: 10.1038/nature19353

Erratum in

Corrigendum: Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition.
Sciacovelli M, Gonçalves E, Johnson TI, Zecchini VR, da Costa AS, Gaude E, Drubbel AV, Theobald SJ, Abbo SR, Tran MG, Rajeeve V, Cardaci S, Foster S, Yun H, Cutillas P, Warren A, Gnanapragasam V, Gottlieb E, Franze K, Huntly B, Maher ER, Maxwell PH, Saez-Rodriguez J, Frezza C. Sciacovelli M, et al. Nature. 2016 Dec 1;540(7631):150. doi: 10.1038/nature20144. Epub 2016 Oct 19. Nature. 2016. PMID: 27760119 No abstract available.

Abstract

Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation. However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster mir-200ba429, leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Extended Data Figure 1. Characterisation of Fh1-deficient and Fh1-rescued cells.**
a, PCR to assess *Fh1* recombination. The putative genotypes are indicated on the right and are based on the expected size of the genomic PCR amplification products as from Frezza et al. *Fh1^fl/fl* = 470 bp and *Fh1^-/-*= 380 bp. b, Fh1 protein levels measured by western blot of cells of the indicated genotype. Calnexin was used as loading control for western blot. c, Intracellular fumarate levels measured by LCMS and normalised to total ion count. Results were obtained from 4 independent cultures and are indicated as average ± S.D.. p-values were calculated from one-way ANOVA. d, Oxygen Consumption rate (OCR) and Extracellular Acidification rate (ECAR) assessed using the Seahorse Extracellular Flux Analyser. Results were obtained from 5 replicate wells and are presented as average ± S.D.. e, Bright field images of cells of the indicated phenotype. Bar = 400 µm. Western blot and gel sources are presented in Supplementary Figure 1. Raw data are presented in SI Table 2. *P ≤0.05, **P ≤0.01, ***P ≤0.001, ****P≤0.0001. f, Schematic representation of the proposed link between loss of FH, fumarate accumulation, and epigenetic suppression of the antimetastatic cluster of miRNA *miR-200*. Upon accumulation of fumarate as a result of FH inactivation, the TET-mediated demethylation of the *miR-200ba429* cluster is inhibited, leading to their epigenetic suppression. As a consequence, Zeb1/2 are de-repressed, eliciting a signalling cascade that leads to EMT.

**Extended Data Figure 2. EMT signature in *Fh1^-/-* cells.**
a, Volcano plot of RNA-seq analysis. Gene expression was normalised to *Fh1^fl/fl* or *Fh1^-/-+pFh1* cells as indicated. b, c, Gene set enrichment analysis (b) and EMT enrichment score (c) of the indicated cell lines.

**Extended Data Figure 3. EMT signature in UOK262 cells.**
a, Gene set enrichment analysis and EMT enrichment score of the indicated cell lines. Gene expression was normalised to UOK262pFH. b, c, mRNA expression measured by qPCR (b) and protein levels measured by western blot (c) of the indicated EMT markers. d, Immunofluorescence staining for Vimentin and E-Cadherin. DAPI was used as marker for cell nuclei. Scale Bar = 25 µm. e, Cell migration rate. Results were obtained from 14 replicate wells and presented as mean ± S.D.. f, mRNA expression of EMT-related transcription factors *ZEB1* and *ZEB2* from RNA-seq data as in Fig. 1a. g, Expression levels of the indicated miRNAs measured by qPCR. h, Volcano plot of miRNA profiling. All qPCR experiments were obtained from 3 independent experiments and presented as RQ with max values, normalised to *β-actin* or *RNU6B/SNORD61* as endogenous control for mRNA and miRNA analyses, respectively. *P ≤0.05, **P ≤0.01, ***P ≤0.001, ****P≤0.0001. Western blot sources are presented in Supplementary Figure 1. Raw data are presented in SI Table 2.

**Extended Data Figure 4. EMT features in Fh1-deficient cells are independent from HIF.**
mRNA levels of EMT genes (a) and HIF _target genes (b) in *Fh1^-/-* cells infected with shRNA against HIF1β measured by qPCR. Results were obtained from 3 independent cultures and presented as RQ with max values using *β-actin* as endogenous control. NTC = non-_targeting control. p-values from unpaired t-test are indicated in the graph. *LdhA* = lactate dehydrogenase A; *Pdk1* = pyruvate dehydrogenase kinase 1; *Glut 1* = glucose transporter 1. *P ≤0.05, **P ≤0.01, ***P ≤0.001, ****P≤0.0001. Raw data are presented in SI Table 2.

**Extended Data Figure 5. EMT signature in Fh1-reconstituted cells.**
a, Fh1 protein levels measured by western blot. Calnexin was used as loading control. b, Intracellular fumarate levels the measured by LCMS. Data are presented as average ± S.D.. c, Representative bright field images of cells of the indicated genotype. Scale Bar = 400 µm. d, e, mRNA expression measured by qPCR (d) and protein levels measured by western blot (e) of the indicated EMT markers. f, Average speed of cells calculated after tracking cells for 3 hours as in Fig. 1g. Results were generated from 3 independent cultures. g, mRNA expression of EMT-related transcription factors. *β-actin* was used as endogenous control. EV = empty vector. h, Expression levels of the indicated miRNAs measured by qPCR and normalised to *Snord95* and *Snord61* as endogenous control. All qPCR results were obtained from 3 independent cultures and presented as RQ with max values. *P ≤0.05, **P ≤0.01, ***P ≤0.001, ****P≤0.0001. Western blot sources are presented in Supplementary Figure 1. Raw data are presented in SI Table 2.

**Extended Data Fig. 6. Role of Tets and Histone Demethylases in EMT induction.**
a, Expression levels of *Tet1-3* in *Fh1 ^fl/fl* from RNA-seq data. b, d, Expression levels of *Tet2/3* **(b)**, *miRNA200* (c), and *E-cadherin* (d) in *Fh1 ^fl/fl* cells upon combined silencing of *Tet2* and *Tet3*. The results are presented as RQ with max values obtained from technical replicates. *β-actin* and *Snord61* were used as endogenous control for mRNA and miRNA, respectively. e, Expression levels of the indicated miRNAs upon inhibition of histone demethylases by GSK J4. *Snord61* and *Snord95* were used as endogenous controls. f, Expression of the indicated miRNAs in *Fh1^-/-* cells incubated for 24 hours with 5 mM DM-aKG measured by qPCR. Results were obtained from 4 (vehicle) or 5 (*Fh1^-/-CL19*) and 3 (*Fh1^-/-CL1*) (DM-aKG) independent cultures and presented as RQ with max values, normalised to *Snord95* as endogenous control. *P ≤0.05, **P ≤0.01, ***P ≤0.001, ****P≤0.0001.

**Extended Data Fig. 7. Characterisation of the regulatory CpG island *CpG43*.**
a, Snapshot of Genome Browser view of genomic DNA around the *miR200ba429* cluster taken from NCBI37/mm9. Tet2 ChIP was obtained from GSE41720, sample GSM1023124. Shaded rectangles indicate *miR-200ba429* and *CpG43*. b, ChIP-PCR of the indicated histone marks in a region adjacent *CpG43*. Data were obtained from 3 independent cultures and are presented as average ± S.D.. p-values from unpaired t-tests are indicated in the graph. c, Expression levels of H3 histone marks in cells of the indicated genotypes measured by western blot. H3 used as loading control. d, 3C data of the genomic region adjacent to *CpG43* analysed in *Fh1^fl/fl* cells. The position of *CpG30* and *CpG43,* and of the predicted restriction sites are indicated in the graph. Results were generated from 2 independent cultures. e, DNA methylation of the *CpG43* assessed by qPCR using OneStep qMethyl kit. Data were obtained from 3 independent experiments and normalised to methylation levels of the region in *Fh1^fl/fl*. Data are presented as average ± S.E.M.. f, ChIP-PCR of Tets binding to *CpG43*. Data were obtained from three replicates and are presented as average ± S.D.. g, 5hmc nuclear staining assessed by immunofluorescence using 5hmc antibody. Nuclear staining was quantified using Image J and an average of 120 cells was used per genotype. p-values from One-way ANOVA test. Representative images of 5hmc staining are shown. DAPI is used to indicate the nuclei. Bar = 20 μm. *P ≤0.05, **P ≤0.01, ***P ≤0.001, ****P≤0.0001. Western blot sources are presented in Supplementary Figure 1. Raw data are presented in SI Table 2.

**Extended Data Fig. 8. Monomethyl Fumarate (MMF) triggers EMT in FH-proficient cells.**
a, Bright field images of cells treated for 6 weeks with MMF. Arrows indicate the typical protrusion of cells of mesenchymal phenotype. Bar = 400 µm. b, Oxygen consumption rate of the indicated cell lines treated chronically with MMF (as in Fig. 3). See Methods for drugs concentrations. OCR was normalised to total protein content. Results were obtained from 6 (for mouse cells) or 8 (for human cells) wells ± SD.. c, Hive plot of metabolomics data of mouse and human cells treated with MMF (as in Fig. 3). All identified metabolites are included on the y-axis and grouped into human (pink) and mouse (green) cells. Metabolites accumulated (right x-axis) or depleted (left x-axis) in MMF-treated cells versus control are indicated by a connecting arc and their fold-change is colour-coded. Metabolites accumulated commonly across the two cell lines are highlighted with a solid line. 2SC: 2-succinic-cysteine, succGSH: succinic-GSH. Raw data are presented in SI Table 2. Raw metabolomic data are presented in SI Table 3.

**Extended Data Fig. 9. Succinate triggers EMT in Sdhb-deficient cells.**
a, Intracellular succinate levels after incubation with 4 mM MMS measured by LCMS. Data are presented as average ±S.D.. b, c, Intracellular succinate (b) and succGSH (c) levels in Sdhb-deficient cells measured by LMCS. Data are presented as average ±S.D.. d, Bright field images of cells of the indicated genotype. Bar = 400 µm. e, Gene set enrichment analysis and EMT enrichment score from expression analysis of the indicated cell lines. f, g, miRNA expression levels normalised to *Snord61* and *Snord95* as endogenous control (f) and *CpG43* methylation (g). Experiments were performed as in Fig. 2b and 2d, respectively. *P ≤0.05, **P ≤0.01, ***P ≤0.001, ****P≤0.0001. Gel sources are presented in Supplementary Figure 1. Raw data are presented in SI Table 2.

**Extended Data Fig. 10. Expression of FH and EMT markers in kidney cancer.**
a, Expression levels of *Vimentin* and *E-Cadherin* in HLRCC patients obtained from Ooi et al. b, Immunohistochemistry staining of Vimentin and E-Cadherin (left), and TET1 and TET2 (right) in HLRCC patients obtained as in Fig. 4a. Bar = 100 µm. The insert in the left panel indicate a 3X digital magnification, Bar = 50 µm. c, Gene set enrichment analysis and EMT enrichment score from RNA-seq data of papillary renal cell carcinoma (KIRP) obtained by Linehan et al. d, Volcano plot of MIRNA expression in KIRP. e, Kaplan-Meier curve of KIRP patients separated according to FH expression. f, *Vimentin* and *E-Cadherin* expression in FH-mutant KIRP compared to normal renal tissue. g, Frequency of mutations in FH and *TET1, TET2* and *TET3* in KIRP analysed using NCBO BioPortal. Only cancers with mutations in the indicated genes are shown. h, Kaplan-Meier curve of FH-wild type and FH-mutant KIRP. i, Expression levels of FH, *Vimentin,* and *E-Cadherin* in clear cell renal cell carcinoma (KIRC) obtained from TCGA dataset. j, Volcano plot of miRNA expression in KIRC. j, Kaplan-Meier curve of KIRC patients separated according to FH expression.

**Figure 1. FH-deficient cells display mesenchymal features.**
a, b, Volcano plots of proteomics (a) and RNA-seq (b) experiments. FDR = false discovery rate. c, d, mRNA expression measured by qPCR (c) and protein levels measured by western blot (d) of EMT markers. e, Immunofluorescence staining for vimentin and E-cadherin. Scale Bar = 25 µm. f, Cells migration assay. Data indicate cell index at 17 hours. Results were obtained from 4 (*Fh1 ^-/-+pFh1*) or 3 replicate wells and presented as mean ± S.D. p-value was calculated using One way-ANOVA. g, Average speed of cells. p-value was calculated using Mann-Whitney test. Results were obtained from 3 independent cultures. h, mRNA expression of EMT-related transcription factors measured by qPCR. i, Western blot analysis of Zeb1. Calnexin was used as loading control. All qPCR results were obtained from 3 independent cultures and presented as RQ with max values, normalised for *β-actin*. p-values was calculated using unpaired t-test. *P ≤0.05, **P ≤0.01, ***P ≤0.001, ****P≤0.0001. For western blot source data, see Supplementary Figure 1. For Raw data see SI Table 2.

**Figure 2. Loss of Fh1 triggers epigenetic suppression of *miR-200*.**
a, Volcano plot of miRNA profiling. b, miRNAs expression measured by qPCR. Date were normalised to *Snord95*. c, miRNAs and EMT markers expression in Fh1^-/- cells expressing *miR*-*200ba429*. *β-actin* and *Snord95* were used as endogenous control for mRNA and miRNA, respectively. NTC= non-_targeting control. d, Methylation-specific PCR of *CpG43*. U = un-methylated; M = methylated CpG island. The *miR-200ba429* cluster (blue) and *CpG43* (green) are represented in the schematic. qPCR results were obtained from at least 3 independent cultures and presented as RQ with max values. p-values was calculated using unpaired t-test. *P ≤0.05, **P ≤0.01, ***P ≤0.001, ****P≤0.0001. For gel source data, see Supplementary Figure 1. For Raw data see SI Table 2.

**Figure 3. Fumarate triggers EMT in FH-proficient cells.**
miRNA methylation (a) and expression (b, e); EMT transcription factors (c, f) and EMT markers (d, g) levels from MMF-treated cells. Results were obtained from 3 independent cultures. qPCRs are presented as RQ with max values, normalised for *Snord95* (mouse) or *SNORD95* (human) for miRNAs, and for *β-actin* for mRNA. p-values were calculated using unpaired t-test. *P ≤0.05, **P ≤0.01, ***P ≤0.001, ****P≤0.0001. For gel source data, see Supplementary Figure 1. For Raw data see SI Table 2.

**Figure 4. Loss of FH correlates with EMT signature in renal cancers.**
**a-c**, Metabolomic analysis (a), 5hmc levels in DNA (b), and MIRNAs expression (c) in tumour samples from two HLRCC patients. Results were obtained from 4 technical replicates per sample. qPCRs are presented as RQ with max values, normalised for *RNU6B* and *SNORD61*. d, e, Expression levels (d), and promoter methylation (e) of the indicated *MIRNAs* in KIRP patients f, g, *Vimentin* (f) and *E-Cadherin* (g) expression in clear cell renal cell carcinoma (KIRC) patients. For Raw data see SI Table 2.

See this image and copyright information in PMC

Comment in

Oncometabolite Accumulation and Epithelial-to-Mesenchymal Transition: The Turn of Fumarate.
Janin M, Esteller M. Janin M, et al. Cell Metab. 2016 Oct 11;24(4):529-530. doi: 10.1016/j.cmet.2016.09.020. Cell Metab. 2016. PMID: 27732835

Cited by

Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy.
Cuyàs E, Verdura S, Martin-Castillo B, Alarcón T, Lupu R, Bosch-Barrera J, Menendez JA. Cuyàs E, et al. Cancers (Basel). 2020 Jul 2;12(7):1757. doi: 10.3390/cancers12071757. Cancers (Basel). 2020. PMID: 32630618 Free PMC article.
A break in mitochondrial endosymbiosis as a basis for inflammatory diseases.
Murphy MP, O'Neill LAJ. Murphy MP, et al. Nature. 2024 Feb;626(7998):271-279. doi: 10.1038/s41586-023-06866-z. Epub 2024 Feb 7. Nature. 2024. PMID: 38326590 Review.
Nitrogen Trapping as a Therapeutic Strategy in Tumors with Mitochondrial Dysfunction.
Madala HR, Helenius IT, Zhou W, Mills E, Zhang Y, Liu Y, Metelo AM, Kelley ML, Punganuru S, Kim KB, Olenchock B, Rhee E, Intlekofer AM, Iliopoulos O, Chouchani E, Yeh JJ. Madala HR, et al. Cancer Res. 2020 Sep 1;80(17):3492-3506. doi: 10.1158/0008-5472.CAN-20-0246. Epub 2020 Jul 10. Cancer Res. 2020. PMID: 32651261 Free PMC article.
Mitochondrial metabolism and cancer metastasis.
Yu D, Liu C, Guo L. Yu D, et al. Ann Transl Med. 2020 Jul;8(14):904. doi: 10.21037/atm.2020.03.42. Ann Transl Med. 2020. PMID: 32793748 Free PMC article. Review.
Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis.
Wang YP, Sharda A, Xu SN, van Gastel N, Man CH, Choi U, Leong WZ, Li X, Scadden DT. Wang YP, et al. Cell Metab. 2021 May 4;33(5):1027-1041.e8. doi: 10.1016/j.cmet.2021.03.003. Epub 2021 Mar 25. Cell Metab. 2021. PMID: 33770508 Free PMC article.

See all "Cited by" articles

References

1. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30:406–410. - PubMed
1. Schmidt LS, Linehan WM. Hereditary leiomyomatosis and renal cell carcinoma. Int J Nephrol Renovasc Dis. 2014;7:253–260. - PMC - PubMed
1. Yang M, Soga T, Pollard PJ, Adam J. The emerging role of fumarate as an oncometabolite. Front Oncol. 2012;2:85. doi: 10.3389/fonc.2012.00085. - DOI - PMC - PubMed
1. Laukka T, Mariani CJ, Ihantola T, Cao JZ, Hokkanen J, Kaelin WG, Jr, Godley LA, Koivunen P. Fumarate and Succinate Regulate Expression of Hypoxia-Inducible Genes via TET Enzymes. J Biol Chem. 2015 - PMC - PubMed
1. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012;26:1326–1338. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Research Materials
- Addgene Non-profit plasmid repository

[1] Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30:406–410. - PubMed

[2] Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30:406–410. - PubMed

[3] Schmidt LS, Linehan WM. Hereditary leiomyomatosis and renal cell carcinoma. Int J Nephrol Renovasc Dis. 2014;7:253–260. - PMC - PubMed

[4] Schmidt LS, Linehan WM. Hereditary leiomyomatosis and renal cell carcinoma. Int J Nephrol Renovasc Dis. 2014;7:253–260. - PMC - PubMed

[5] Yang M, Soga T, Pollard PJ, Adam J. The emerging role of fumarate as an oncometabolite. Front Oncol. 2012;2:85. doi: 10.3389/fonc.2012.00085. - DOI - PMC - PubMed

[6] Yang M, Soga T, Pollard PJ, Adam J. The emerging role of fumarate as an oncometabolite. Front Oncol. 2012;2:85. doi: 10.3389/fonc.2012.00085. - DOI - PMC - PubMed

[7] Laukka T, Mariani CJ, Ihantola T, Cao JZ, Hokkanen J, Kaelin WG, Jr, Godley LA, Koivunen P. Fumarate and Succinate Regulate Expression of Hypoxia-Inducible Genes via TET Enzymes. J Biol Chem. 2015 - PMC - PubMed

[8] Laukka T, Mariani CJ, Ihantola T, Cao JZ, Hokkanen J, Kaelin WG, Jr, Godley LA, Koivunen P. Fumarate and Succinate Regulate Expression of Hypoxia-Inducible Genes via TET Enzymes. J Biol Chem. 2015 - PMC - PubMed

[9] Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012;26:1326–1338. - PMC - PubMed

[10] Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012;26:1326–1338. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition

Affiliations

Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Research Materials

Erratum in

Abstract

Conflict of interest statement

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Research Materials