The DOI matches its Crossref record; 58 of the 60 references it cites were found in a registry or an index.
SDH Mutations Establish a Hypermethylator Phenotype in Paraganglioma
Open accessAbstract
Paragangliomas are neuroendocrine tumors frequently associated with mutations in RET, NF1, VHL, and succinate dehydrogenase (SDHx) genes. Methylome analysis of a large paraganglioma cohort identified three stable clusters, associated with distinct clinical features and mutational status. SDHx-related tumors displayed a hypermethylator phenotype, associated with downregulation of key genes involved in neuroendocrine differentiation. Succinate accumulation in SDH-deficient mouse chromaffin cells led to DNA hypermethylation by inhibition of 2-OG-dependent histone and DNA demethylases and established a migratory phenotype reversed by decitabine treatment. Epigenetic silencing was particularly severe in SDHB-mutated tumors, potentially explaining their malignancy. Finally, inactivating FH mutations were identified in the only hypermethylated tumor without SDHx mutations. These findings emphasize the interplay between the Krebs cycle, epigenomic changes, and cancer.
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“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 Letouze et al., 2013
In the citing paper
“In cancer cells, mutations in succinate dehydrogenase subunit B (SDHB) cause susceptibility to familial pheochromocytoma99 and familial paraganglioma100 as well as gastrointestinal stromal tumors101.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [100]
In the citing paper
“As succinate accumulates via the inhibition of the 2-OGDD enzyme, epigenetic modification acts in the process of cell transformation into a hypermethylated phenotype100.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [100]
In the citing paper
“Although additional studies are needed, ample experimental data support the recognition of R-2-HG, succinate, and fumarate as oncometabolites.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [100]
In the citing paper
“Several studies have shown that SDH-deficient cells exhibit increased tumorigenesis and that this increase is reversed by the addition of α-KG, supporting the idea that succinate accumulation contributes to tumorigenesis through epigenetic modification100.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [100]
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 Letouze et al., 2013
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“, 2014); (ii) colorectal cancer, through the activation of the transforming growth factor beta (TGF-ß)/Snail1/small mothers against decapentaplegic (SMAD3 and SMAD4) pathway (Wang, Chen, & Wu, 2016); and (iii) PGL/PCC, through modulation of the expression of different EMT markers, including Twist family transcription…”
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InfluentialSelf-citationPamporaki, C., Prodanov, T., Meuter, L., Berends, A. M. A., Bechmann, N., Constantinescu, G. A., Beuschlein, F., Remde, H., Januszewicz, A., Kerstens, M. N., et al. (2022) · European Journal of Cancer · doi:10.1016/j.ejca.2022.03.032 · Cited by 47
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“This enzyme is involved in succinate to fumarate oxidation and electron transport [150, 151].”
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Jasim, S., & Jiménez, C. (2019) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2019.101354 · Cited by 49
Pellerino, A., Verdijk, R. M., Nichelli, L., Andratschke, N. H., Idbaïh, A., & Goldbrunner, R. (2023) · Cancers · doi:10.3390/cancers15071930 · Cited by 46
Pheochromocytoma and paraganglioma
Burnichon, N., Buffet, A., & Gimenez‐Roqueplo, A. (2015) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000249 · Cited by 46
Self-citationReview of sequencing platforms and their applications in phaeochromocytoma and paragangliomas
Pillai, S., Gopalan, V., & Lam, A. K.-Y. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.05.005 · Cited by 46
Aldera, A. P., & Govender, D. (2017) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2017-204677 · Cited by 46
Clinical evaluation and treatment of phaeochromocytoma
Davison, A. S., Jones, D. M., Ruthven, S., Helliwell, T. R., & Shore, S. (2017) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/0004563217739931 · Cited by 46
Sun, X., & Zhu, M. J. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700932 · Cited by 46
Pheochromocytomas and Paragangliomas: From Genetic Diversity to Targeted Therapies
Pang, Y. K., Liu, Y., Pacák, K., & Yang, C. (2019) · Cancers · doi:10.3390/cancers11040436 · Cited by 48
“In some tumor cells, the expression of O6-methylguanine-DNA methyltransferase (MGMT) can directly remove the alkyl group from O6-guanine, resulting in resistance to TMZ.”
BackgroundInfluentialRescue of TCA Cycle Dysfunction for Cancer Therapy
Marquez, J. C., Flores, J., Kim, A. H., Nyamaa, B., Nguyen, A. T. T., Park, N., & Han, J. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8122161 · Cited by 47
“AG-221 IDH2 Catalyze conversion of isocitrate to α-ketoglutarate inhibit Clinical trial: acute myeloid leukemia and myelodysplastic syndrome patients [86]”
BackgroundMethodSelf-citationMetabolite regulation of epigenetics in cancer
Wang, P., Chen, L., Xiong, Y., & Ye, D. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114815 · Cited by 50
“64,65 Like D-2-HG, fumarate and succinate disrupt cell differentiation and cell fate establishment and cause cell transformation.”
Research into cancer metabolomics: Towards a clinical metamorphosis
Olivares, O., Däbritz, J. H. M., King, A., Gottlieb, E., & Halsey, C. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.09.008 · Cited by 45
“SDH inactivation is increasingly observed in other malignancies [73-75] and may reach diagnostic relevance as soon as compounds that interfere with the resulting epigenetic [76] or”
BackgroundMeunier, L., Hirsch, T. Z., Caruso, S., Imbeaud, S., Bayard, Q., Roehrig, A., Couchy, G., Nault, J., Llovet, J. M., Blanc, J., et al. (2021) · Hepatology · doi:10.1002/hep.31796 · Cited by 52
Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme
Esteban-Amo, M. J., Jiménez-Cuadrado, P., Serrano‐Lorenzo, P., de la Fuente, M. Á., & Simarro, M. (2024) · Biomedicines · doi:10.3390/biomedicines12092050 · Cited by 51
Tarhonskaya, H., Nowak, R. P., Johansson, C., Szykowska, A., Tumber, A., Hancock, R. L., Lang, P. A., Flashman, E., Oppermann, U. C. T., Schofield, C. J., et al. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.08.007 · Cited by 45
“Accumulation of D-2HG in cells has been reported to affect the H3K9 and H3K27 methylation status [38, 39] and SDH/FH mutant tumours have been linked to global increases in DNA methylation/hydroxymethylation levels [40, 41].”
BackgroundLiu, Y., Pang, Y. K., Zhu, B., Uher, O., Caisová, V., Huynh, T., Taïeb, D., Vanova, K. H., Ghayee, H. K., Neužil, J., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2335 · Cited by 46
A New Specific Succinate-Glutamate Metabolomic Hallmark in Sdhx-Related Paragangliomas
Impériale, A., Moussallieh, F., Sebag, F. A., Brunaud, L., Barlier, A., Elbayed, K., Bachellier, P., Goichot, B., Pacák, K., Namer, I. J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080539 · Cited by 43
“These tumors accumulate succinate, which inhibits 2-oxoglutarate-dependent histone and DNA demethylase enzymes, resulting in epigenetic modifications [8].”
BackgroundAnalyzing Tumor Metabolism In Vivo
Faubert, B., & DeBerardinis, R. J. (2016) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-050216-121954 · Cited by 44
“These dioxygenases include histone demethylases, 5-methylcytosine hydroxylases, and prolyl hydroxylases that target hypoxia-inducible factor-α subunits for degradation (Isaacs et al. 2005, Letouze et al. 2013, Sciacovelli et al. 2016, Selak et al. 2005, Xiao et al. 2012).”
BackgroundMolecular markers of paragangliomas/pheochromocytomas
Zhikrivetskaya, S. O., Snezhkina, A. V., Zaretsky, A. R., Alekseev, B. Y., Pokrovsky, A. V., Golovyuk, A. L., Melnikova, N. V., Stepanov, O. A., Kalinin, D. V., Moskalev, A., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.15201 · Cited by 45
“Mutations in FH are associated with hereditary leiomyomatosis and renal cancer [105]; additionally, mutations were also found in some pheochromocytomas that resembled SDH-mutant tumors in their transcription and methylation profiles [98].”
BackgroundCasey, R. T., Warren, A. Y., Martín, J., Challis, B., Rattenberry, E., Whitworth, J., Andrews, K. A., Roberts, T., Clark, G. R., West, H. D., et al. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-00562 · Cited by 43
“A B No Unilateral RCC PC, brother (44) 7, 33 SDHB Exon 1 deletion B No Unilateral RCC (36) M RCC, brother (25) 39”
InfluentialMetabolic Signaling to Epigenetic Alterations in Cancer
Kim, J., & Yeom, Y. I. (2017) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2017.185 · Cited by 45
“Consistently, DNA hypermethylation was observed in paragangliomas harboring the SDH mutation (Letouze et al., 2013).”
BackgroundMetabolism and Transcription in Cancer: Merging Two Classic Tales
Martín-Martín, N., Carracedo, A., & Torrano, V. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2017.00119 · Cited by 43
“Deficiency of SDH is associated with global DNAmethylation changes (Killian et al., 2013) and the downregulation of neuroendocrine differentiation genes linked to a migratory phenotype (Letouze et al., 2013).”
BackgroundZhou, Z., Ibekwe, E., & Chornenkyy, Y. (2018) · Antioxidants · doi:10.3390/antiox7010016 · Cited by 44
Fankhauser, M., Bechmann, N., Lauseker, M., Goncalves, J., Favier, J., Klink, B., William, D., Gieldon, L., Maurer, J., Spöttl, G., et al. (2019) · Endocrinology · doi:10.1210/en.2019-00410 · Cited by 43
“Based on these data, we have investigated the anti-tumor potential of a variety of both targeted and chemotherapeutic agents and their combinations, and their impact on cellular signaling pathways, in well-validated murine PCC cell line models and a murine Sdhb knockout (Sdhb-/-) cell line (the best available cell lin…”
BackgroundMethodInfluentialSelf-citationPeritoneal Implantation of Pheochromocytoma Following Tumor Capsule Rupture During Surgery
Rafat, C., Zinzindohoué, F., Hernigou, A., Hignette, C., Favier, J., Tenenbaum, F., Gimenez‐Roqueplo, A., Plouin, P., & Amar, L. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1975 · Cited by 43
“The absence of such mutations in case B led to further analysis revealing a somatic mutation of the fumarate hydratase (FH) gene (13).”
BackgroundSelf-citationRubas, N. C., Torres, A., & Maunakea, A. K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178658 · Cited by 46
“Among their diverse biological effects, SCFAs are best known for their role as histone deacetylase (HDAC) inhibitors, thereby promoting a more open chromatin configuration and enhancing gene expression [66,68].”
Toledo, R. A., & Dahia, P. L. M. (2015) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000150 · Cited by 42
Gerometabolites: The pseudohypoxic aging side of cancer oncometabolites
Menéndez, J. A., Alarcón, T., & Joven, J. (2014) · Cell Cycle · doi:10.4161/cc.28079 · Cited by 42
“Thus, proto-oncogenes and tumor suppressors possibly originated through evolution as components of metabolic regulation and, more importantly, so-called oncometabolites can directly impair the normal epigenetic regulation of cell differentiation and alter cell signaling to drive cellular transformation and oncogenesis…”
BackgroundBailey, P. S. J., & Nathan, J. A. (2018) · Biomedicines · doi:10.3390/biomedicines6020060 · Cited by 41
“Interestingly, these tumours showed particular susceptibility to treatment with inhibitors of DNA methlyation [108].”
BackgroundResultInfluentialWhat Have We Learned from Molecular Biology of Paragangliomas and Pheochromocytomas?
Papathomas, T. G., Suurd, D. P. D., Pacák, K., Tischler, A. S., Vriens, M. R., Lam, A. K.-Y., & de Krijger, R. R. (2021) · Endocrine Pathology · doi:10.1007/s12022-020-09658-7 · Cited by 40
Targeted therapy in SDH- deficient GIST
Nannini, M., Rizzo, A., Indio, V., Schipani, A., Astolfi, A., & Pantaleo, M. A. (2021) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359211023278 · Cited by 41
Armstrong, N., Storey, C. M., Noll, S. E., Margulis, K., Soe, M. H., Xu, H., Yeh, B. T., Fishbein, L. M., Kebebew, E., Howitt, B. E., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110453 · Cited by 42
“Succinate inhibition of JmjC enzymes leads to an increase in multiple histone 3 lysine methyl marks, such as H3K9me3, H3K27me3, and H3K4me3 (Letouze et al., 2013; Hoekstra et al., 2015a).”
BackgroundComprehensive Overview of the Amide Linker Modification in the Succinate Dehydrogenase Inhibitors
Zeng, L.-Q., Chen, Q., Wei, G., Chen, W., Zhu, X., & Yang, G. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c05854 · Cited by 40
Toledo, R. A. (2017) · Endocrine Related Cancer · doi:10.1530/erc-16-0479 · Cited by 42
Aghamir, S. M. K., Heshmat, R., Ebrahimi, M., Ketabchi, S. E., Parichehreh-Dizaji, S., & Khatami, F. (2019) · OncoTargets and Therapy · doi:10.2147/ott.s207460 · Cited by 39
Matlac, D. M., Vanova, K. H., Bechmann, N., Richter, S., Inderhees, J., Ghayee, H. K., Ge, G., Abunimer, L., WESLEY, R. A., Aherrahrou, R., et al. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.589451 · Cited by 40
“Other cell models with similarly or even more efficient succinate accumulation have been reported (48, 53, 54), however SUCNR1 expression has not been evaluated.”
BackgroundMechanisms Governing Metabolic Heterogeneity in Breast Cancer and Other Tumors
Patra, S., Elahi, N., Armorer, A., Arunachalam, S., Omala, J., Hamid, I., Ashton, A. W., Joyce, D. A., Jiao, X., & Pestell, R. G. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.700629 · Cited by 43
Mitochondrial Redox Metabolism: The Epicenter of Metabolism during Cancer Progression
Choudhury, F. K. (2021) · Antioxidants · doi:10.3390/antiox10111838 · Cited by 44
Metadata
- Authors
- Letouzé, E., Martinelli, C., Loriot, C., Burnichon, N., Abermil, N., Ottolenghi, C., Janin, M., Menara, M., Nguyen, A. T., Benit, P., Buffet, A., Marcaillou, C., Bertherat, J., Amar, L., Rustin, P., De Reyniès, A., Gimenez-Roqueplo, A.-P., & Favier, J.
- Affiliations
- Inserm (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Hôpital Necker-Enfants Malades (FR)
- IntegraGen (France) (FR)
- Corresponding author
- Favier, Judith
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 23
- Issue
- 6
- Pages
- 739-752
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2061662711
- Semantic Scholar
- 12ff63634482848e635a81bd0e943c6b9634ac9a
- Cited by
- 776
- References
- 60
- Citations by year
- 2026: 41 · 2025: 34 · 2024: 61 · 2023: 55 · 2022: 53 · 2021: 65 · 2020: 53 · 2019: 70 · 2018: 59 · 2017: 79 · 2016: 58 · 2015: 73 · 2014: 50 · 2013: 22
- FWCI
- 66.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agence Nationale de la Recherche
- Core Research for Evolutional Science and Technology
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Clinical Neurology › Neurofibromatosis and Schwannoma Cases
- Keywords
- paraganglioma, succinate dehydrogenase, SDHB mutation, DNA hypermethylation, succinate accumulation, epigenetic silencing, neuroendocrine differentiation, FH mutations, decitabine, chromaffin cells, TCA cycle, tumor malignancy
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Animals, Cell Movement, Child, Female, Glioblastoma, Histones, Humans, Male, Middle Aged, Paraganglioma, Phenotype, Pheochromocytoma, Succinate Dehydrogenase, Colorectal Neoplasms, DNA Methylation, Chromaffin Cells, Gene Silencing, Epigenesis, Genetic, Mice, Gene Knockout Techniques, Transcriptome
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