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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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“(23) Epigenetic ecology suggests that host–pathogen interactions lead to physiological re-programming.”
Petrák, J., Tevosian, S. G., Richter, S., & Ghayee, H. K. (2024) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2024.101935 · Cited by 5
Sanceau, J., Westbrook, R., & Favier, J. (2025) · Annales d Endocrinologie · doi:10.1016/j.ando.2025.101772 · Cited by 5
Self-citationVitamin B12 as a neuroprotectant in neuroinflammation
Cassiano, L. M. G., Oliveira, M. D. S., & Coimbra, R. S. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-89835-5.00038-7 · Cited by 5
Four generations of SDHB-related disease: complexities in management
Srirangalingam, U., LeCain, M., Tufton, N., Akker, S. A., Drake, W. M., & Metcalfe, K. A. (2016) · Familial Cancer · doi:10.1007/s10689-016-9946-9 · Cited by 5
“SDHB gene as a driver of hypermethylation and thus silencing of key genes involved in neuroendocrine differentiation have been proposed [3].”
BackgroundPacák, K., Timmers, H. J. L. M., & Eisenhofer, G. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-18907-1.00110-4 · Cited by 5
The Role of the Metabolome and Non-Coding RNA on Pheochromocytomas and Paragangliomas: An Update
Bouça, B., Bogalho, P., Rizzo, M., & Silva‐Nunes, J. (2022) · Metabolites · doi:10.3390/metabo12020131 · Cited by 5
“In line with these facts, high levels of succinate and fumarate have been shown to be responsible for activating hypoxia signaling pathways and tumorigenic mechanisms such as hypermethylation [20,21].”
BackgroundMaravat, M., Bertrand, M., Landon, C., Fayon, F., Morisset‐Lopez, S., Sarou‐Kanian, V., & Decoville, M. (2021) · Journal of Proteome Research · doi:10.1021/acs.jproteome.1c00304 · Cited by 5
Cerrizuela, S., Vega‐López, G. A., Méndez‐Maldonado, K., Velasco, I., & Aybar, M. J. (2021) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1537 · Cited by 6
Barbolosi, D., Crona, J., Serre, R., Pacák, K., & Taïeb, D. (2018) · PLoS ONE · doi:10.1371/journal.pone.0201303 · Cited by 5
“Activation of the hypoxiainducible factor (HIF) signaling pathway despite normal oxygen supply (also called pseudohypoxia), as well as DNA and histone demethylases inhibition resulting in a hypermethylated genome, are two processes that were uniquely identified to contribute to transformation of a paraganglial cell in…”
BackgroundGlover, M. J., Waguespack, S. G., Campbell, M. T., Varghese, J. M., Ng, C. S., Lu, Y., & Jiménez, C. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag182 · Cited by 4
Genetic variants and down-regulation of CACNA1H in pheochromocytoma
Svahn, F., Höse, K. S., Stenman, A., Liu, Y., Calissendorff, J., Tham, E., Végvári, Á., Zubarev, R. A., Wang, N., Korah, R. M., et al. (2024) · Endocrine Related Cancer · doi:10.1530/erc-23-0061 · Cited by 4
Human and Murine Cell Lines for Adrenocortical Carcinoma and Pheochromocytoma
Luca, E., Abate, A., Wang, K., Bornstein, S. R., Sigala, S., Beuschlein, F., Nölting, S., & Hantel, C. (2024) · Endocrines · doi:10.3390/endocrines5030019 · Cited by 6
“…lack of reliable human cell line models, fresh patient-derived PCC and paraganglioma primary cultures have been established in order to perform multiple drug testing and correlate drug responsiveness of the individual patient-derived tumor primary cultures with the genetic background [131,133,134].”
BackgroundModeling dioxygenase enzyme kinetics in familial paraganglioma
Peters, J. P., Her, Y. F., & Maher, L. J. (2015) · Biology Open · doi:10.1242/bio.013623 · Cited by 4
“In SDH-deficient models, succinate accumulates and stabilizes HIF1α by inhibiting PHD2 (Letouze et al., 2013; MacKenzie et al., 2007; Selak et al., 2005; Xiao et al., 2012).”
BackgroundInfluentialOhshima, K., Oi, R., Okuzaki, D., Motooka, D., Shinohara, M., Nojima, S., & Morii, E. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01582-9 · Cited by 4
Imaging pheochromocytoma in small animals: preclinical models to improve diagnosis and treatment
Mohr, H., Foscarini, A., Steiger, K., Ballke, S., Rischpler, C., Schilling, F., & Pellegata, N. S. (2021) · EJNMMI Research · doi:10.1186/s13550-021-00855-x · Cited by 4
“Mechanistically, it has been demonstrated that in SDHx-mutated tumors, which are more often metastatic, the accumulation of oncometabolites inhibiting ten–eleven translocation (TET) methylcytosine dioxygenases induces hypermethylation and suppression of gene expression [38].”
BackgroundSun, J. K., Wong, G. C., & Chow, H. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15881 · Cited by 4
Precision Medicine in Adrenal Disorders: the Next Generation
Ghayee, H. K., Vinik, A. I., & Pacák, K. (2017) · Endocrine Practice · doi:10.4158/ep161716.ra · Cited by 4
“Such PCC/PGL tumors have a succinate dehydrogenase subunit B (SDHB) mutation, thereby affecting types of treatment options inpatients presenting with metastases (17).”
BackgroundARHI is a novel epigenetic silenced tumor suppressor in sporadic pheochromocytoma
Wang, D., Li, S., Wang, L., Zhao, L., Xiang, B., Li, Y., Shan, B., & Liu, J. (2017) · Oncotarget · doi:10.18632/oncotarget.21149 · Cited by 4
“Drugs targeting epigenetic pathways might constitute useful alternative treatments in PCC [44, 49].”
Role of Succinate Dehydrogenase in Cellular Respiration
Viswalingam, V., & Kumar, D. (2025) · Springer eBooks · doi:10.1007/978-981-96-6831-1_3 · Cited by 3
Xian, J., Pan, X., Kang, Y., Zheng, L., Yin, X., Zhang, M., Wei, Y., Tan, J., Zhang, M., Nie, L., et al. (2025) · British Journal of Cancer · doi:10.1038/s41416-025-03195-y · Cited by 3
“Studies on SDH-de fi cient cancer cells and RCC cells treated with fumarate indicate that the administration of α -KG can reverse HIF-induced pseudohypoxia-driven and 5-methylcytosine (5mc) accumulation by restoring the activity of aKGDDs [26, 27].”
Gut microbiota and metabolomic alterations in newborns of mothers with gestational diabetes mellitus
Su, W.-H., Wang, Y., Chen, C., Lai, M., Chao, H., Chiang, M., Fu, R.-H., & Yeh, P. (2025) · Korean Journal of Pediatrics · doi:10.3345/cep.2025.01074 · Cited by 4
Cubiella, T., Alba‐Linares, J. J., San‐Juan‐Guardado, J., Suárez‐Priede, Á., Gomez-Suarez, N., Tous, M. D. C., Bancos, I., Villabona, C. M., Piñol, T. S., Tena, I., et al. (2026) · Communications Biology · doi:10.1038/s42003-026-09543-9 · Cited by 3
“However, germline mutations in SDHB , SDHD , SDHA , or SDHC (collectively SDHx ) disrupt this process, leading to oncometabolite accumulation that drives epigenetic reprogramming 6,7 and activation of hypoxia-inducible factor (HIF) target genes 8 – 10 .”
InfluentialEpigenetics and disease progression in neuroendocrine neoplasms
Lobato, E. C., Lafranchi, A., Freitas-Castro, F., Fagundes, G. F. C., Sadiković, B., Lines, K. E., & Almeida, M. Q. (2026) · Endocrine Reviews · doi:10.1210/endrev/bnag005 · Cited by 3
Zhao, Y. (2026) · Biogerontology · doi:10.1007/s10522-026-10410-7 · Cited by 3
“By inhibiting TET, succinate accumulation can lead to DNA hypermethylation; by inhibiting JMJD, it can lead to histone hypermethylation (Letouzé et al. 2013).”
Chinopoulos, C. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104224 · Cited by 3
Tiny Messengers, Actionable Targets: sEV-Driven Epigenetic Changes in Cancer
Verma, N., Arora, S., & Croghan, K. (2026) · Targets · doi:10.3390/targets4030030 · Cited by 5
Metabolic basis of cardiac dysfunction in cancer patients
Figueiredo, J. C., Bhowmick, N. A., & Karlstaedt, A. (2024) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000001118 · Cited by 3
Rana, H. Q., Koeller, D. R., Walker, M., Unal, B., Levine, A. S., Chittenden, A. B., Isidro, R. A., Hayes, C. P., Manam, M. D., Buehler, R. M., et al. (2024) · Cancers · doi:10.3390/cancers16050947 · Cited by 3
“Indeed, hyperme-thylation has been reported in SDHx -related tumors as an oncogenic mechanism of SDH inactivation [22,23], and SDHC promoter methylation has been reported in SDHx wild-type PGLs with loss of SDHB by IHC [24].”
BackgroundKhatami, F., Reis, L. O., Ebrahimi, M., Nasiri, S., Tavangar, S. M., Pishkuhi, M. A., Shafiee, G., Heshmat, R., & Aghamir, S. M. K. (2024) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-024-01466-8 · Cited by 3
“M1 comprises tumors with SDHx mutations and hypermethylation, M2 VHL -mutated tumors, and M3 tumors with NF1 and RET mutations and hypomethylation [11, 19].”
Genetics of urinary bladder paragangliomas: a multi-center study of a Chinese cohort
Jiang, J., Pang, Y., Luo, R., Wei, Y., Zhang, J., Li, M., Xu, Y., Teng, X., Wu, H., Guan, H., et al. (2024) · Journal of Endocrinological Investigation · doi:10.1007/s40618-024-02509-w · Cited by 3
“FH loss of function results in accumulation of fumarate and a hypermethylation phenotype [19].”
Vanova, K. H., Uher, O., Kraus, M., Miklovicova, S., Hönigová, K., Gwiezdzinski, S., Garrett, T. J., Ghayee, H. K., Masařík, M., Wang, H., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217969 · Cited by 3
Tumor Cell Complexity and Metabolic Flexibility in Tumorigenesis and Metastasis
Berridge, M. V., & Herst, P. M. (2015) · Springer eBooks · doi:10.1007/978-3-7091-1824-5_2 · Cited by 3
Genetic changes in the FH gene cause vagal paraganglioma
Snezhkina, A. V., Pavlov, V., Kalinin, D. V., Pudova, E. A., Krasnov, G. S., Ayupova, A. F., Kobelyatskaya, A. A., Dmitriev, A. A., Atiakshin, D., Fedorova, M. S., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1381093 · Cited by 3
“Only four cases of FH -mutated HNPGLs (three carotid body tumors and one case of VPGL - the index case) have been reported to date (14, 45, 47).”
Background
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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