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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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“Inactivation of SDHB reduces function of the succinate dehydrogenase complex, leading to activation of the hypoxia-inducible pathway and a pseudohypoxic state characterised by increased angiogenesis, growth and expression of mitogenic factors,(26) but also to DNA hypermethylation, which is believed to provide a furthe…”
BackgroundSqualene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death
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Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes
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“In addition, several reports suggest that SDHx-related tumors display a hypermethylator phenotype associated with downregulation of key genes involved in neuroendocrine differentiation (46, 47).”
BackgroundThe NGS in PPGL (NGSnPPGL) Study Group, Toledo, R. A., Burnichon, N., Cascón, A., Benn, D. E., Bayley, J., Welander, J., Tops, C. M. J., Firth, H. V., Dwight, T., et al. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.185 · Cited by 275
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“…immediate use in biosynthesis pathways by altering hypoxia-inducible transcription factor (HIF) signaling (Selak et al., 2005; King et al., 2006; Boulahbel et al., 2009) and altering gene expression through epigenetic modifications (Xiao et al., 2012; Letouzé et al., 2013; Waterfall et al., 2014).”
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“It has long been known that SDH-deficient PCC/PGL demonstrate an altered metabolic phenotype: not only through the inactivation of SDH mitochondria function per se , but also via a pseudohypoxic phenotype mediated by the effect of succinate accumulation on the cellular transcriptome 11,12,16 .”
Self-citationMetabolic Reprogramming of Cancer Cells during Tumor Progression and Metastasis
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“In particular, mutations in components of the SDH complex are found in patients with hereditary paraganglioma-pheochromocytoma syndrome [29] and gastrointestinal stromal tumor [30], and mutations in FH are found in hereditary leiomyomatosis and renal cell cancer [27].”
BackgroundIDH1 and IDH2 mutations as novel therapeutic targets: current perspectives
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“Mutations in 3 of the 4 genes (succinate dehydrogenase [SDH] B/C/D) comprising the succinate dehydrogenase (SDH) complex, which participates in the Krebs cycle, converting fumarate to succinate, and as mitochondrial respiratory chain complex II, have been associated with an increased risk of kidney cancer.(114) Patien…”
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“We have already extensively described the DNA methylation changes occurring in the M1 cluster 13 .”
InfluentialSelf-citationRecurrent epimutation of SDHC in gastrointestinal stromal tumors
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Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications
Wei, Q., Qian, Y., Yu, J. Q., & Wong, C. C. (2020) · Oncogene · doi:10.1038/s41388-020-01432-7 · Cited by 193
Janke, R., Dodson, A. E., & Rine, J. (2015) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100814-125544 · Cited by 199
“Recently, more than 100 pheochromocytoma and paraganglioma samples were clustered into three groups based on genome-wide measurements of DNA methylation; in the one group that exhibited hypermethylation at CpG sites, 16 of the 17 tumors contained mutations in SDH genes, whereas the other two groups were associated wit…”
BackgroundInfluentialWhole-Exome Sequencing Identifies MDH2 as a New Familial Paraganglioma Gene
Cascón, A., Comino‐Méndez, I., Currás-Freixes, M., de Cubas, A. A., Contreras, L., Richter, S., Peitzsch, M., Mančíková, V., Inglada‐Pérez, L., Pérez‐Barrios, A., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djv053 · Cited by 204
Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad
Haller, F., Moskalev, E. A., Faucz, F. R., Barthelmeß, S., Wiemann, S., Bieg, M., Assié, G., Bertherat, J. Y., Schaefer, I., Otto, C., et al. (2014) · Endocrine Related Cancer · doi:10.1530/erc-14-0254 · Cited by 189
“Interestingly, no correlation between SDHC methylation and mRNA expression has been reported in that study focusing on familial PGLs with SDH germline mutations (Letouzé et al. 2013).”
InfluentialSelf-citationAn overview of 20 years of genetic studies in pheochromocytoma and paraganglioma
Buffet, A., Burnichon, N., Favier, J., & Gimenez‐Roqueplo, A. (2020) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2020.101416 · Cited by 202
Self-citationApplications of metabolomics to study cancer metabolism
Kaushik, A. K., & DeBerardinis, R. J. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.04.009 · Cited by 179
“In paraganglioma and kidney cells lacking functional SDH, succinate inhibits α-KG dependent dioxygenases, resulting in histone hypermethylation and acquisition of EMT-like migratory phenotypes[50, 51].”
Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas
Fishbein, L. M., Khare, S., Wubbenhorst, B. S., DeSloover, D., D'Andrea, K. P., Merrill, S. L., Cho, N. W., Greenberg, R. A., Else, T., Montone, K. T., et al. (2015) · Nature Communications · doi:10.1038/ncomms7140 · Cited by 193
Aspuria, P.-J. P., Lunt, S. Y., Väremo, L., Vergnes, L., Gozo, M. C., Beach, J. A., Salumbides, B. C., Reue, K., Wiedemeyer, W. R., Nielsen, J., et al. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-21 · Cited by 192
“Interestingly, it has been shown that SDHx mutations are associated with hallmarks of EMT in PCC and PGL as a result of alterations to the epigenome [15,16].”
BackgroundResultInfluentialMetabolic Signaling to the Nucleus in Cancer
Campbell, S. L., & Wellen, K. E. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.07.015 · Cited by 186
Oncometabolites: Unconventional triggers of oncogenic signalling cascades
Sciacovelli, M., & Frezza, C. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.025 · Cited by 184
“Succinate inhibits other aKGDDs, including Ten-Eleven Translocation proteins (TETs), enzymes involved in DNA demethylation [34,35], leading to CpG island hypermethylation [36].”
BackgroundGermline FH Mutations Presenting With Pheochromocytoma
Clark, G. R., Sciacovelli, M., Gaude, E., Walsh, D. M., Kirby, G. A., Simpson, M. A., Trembath, R. C., Berg, J. N., Woodward, E. R., Kinning, E., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1659 · Cited by 185
Cassim, S., Vučetić, M., Ždralević, M., & Pouysségur, J. (2020) · Cancers · doi:10.3390/cancers12051119 · Cited by 183
Welander, J., Stenman, A., Juhlin, C. C., Wiseman, R. W., Bäckdahl, M., Höög, A., Larsson, C., Gimm, O., & Söderkvist, P. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-4375 · Cited by 177
Current Approaches and Recent Developments in the Management of Head and Neck Paragangliomas
Taïeb, D., Kaliski, A., Boedeker, C. C., Martucci, V. L., Fojo, T., Adler, J. R., & Pacák, K. (2014) · Endocrine Reviews · doi:10.1210/er.2014-1026 · Cited by 169
Adapt and conquer: Metabolic flexibility in cancer growth, invasion and evasion
Kreuzaler, P. A., Panina, Y., Segal, J., & Yuneva, M. O. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.08.021 · Cited by 170
“It has a number of other consequences, such as impairing HIF signaling and leading to CpG hypermethylation [73,74], which markedly influence the tumor transcriptome and metabolome.”
BackgroundMetabolic coordination of cell fate by α-ketoglutarate-dependent dioxygenases
Baksh, S. C., & Finley, L. W. S. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.09.010 · Cited by 165
“For example, succinate and fumarate accumulation in cancer cells is linked to HIF stabilization and hypermethylation of DNA as well as multiple histone lysine residues [20,22,23].”
BackgroundMalonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration
Bae, J., Salamon, R. J., Brandt, E. B., Paltzer, W. G., Zhang, Z., Britt, E. C., Hacker, T. A., Fan, J., & Mahmoud, A. I. (2021) · Circulation · doi:10.1161/circulationaha.120.049952 · Cited by 161
Metabolic reprogramming, sensing, and cancer therapy
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Guerra, F., Guaragnella, N., Arbini, A., Bucci, C., Giannattasio, S., & Moro, L. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00295 · Cited by 155
Oncometabolites‐driven tumorigenesis: From genetics to targeted therapy
Morin, A., Letouzé, É., Gimenez‐Roqueplo, A., & Favier, J. (2014) · International Journal of Cancer · doi:10.1002/ijc.29080 · Cited by 162
“For example, we showed that phenylethanolamine N-methyltransferase (PNMT), which is an enzyme crucial to chromaffin cell differentiation, is massively downregulated by methylation in PGL/PCC harboring SDHx mutations.(57) Finally, genes that are hypermethylated in cancer are also frequently involved in cellular reprogr…”
BackgroundResultInfluentialSelf-citationThe Metabolic Fates of Pyruvate in Normal and Neoplastic Cells
Prochownik, E. V., & Wang, H. (2021) · Cells · doi:10.3390/cells10040762 · Cited by 150
Oncometabolites: tailoring our genes
Nowicki, S., & Gottlieb, E. (2015) · FEBS Journal · doi:10.1111/febs.13295 · Cited by 148
Toledo, R. A., Qin, Y., Cheng, Z.-M., Gao, Q., Iwata, S., Silva, G. M., Prasad, M. L., Ocal, I. T., Rao, S. N., D, N. A. M., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1841 · Cited by 146
“Indeed, epigenetic changes associated with enhancedDNA andhistonemethylation have been linked to loss-of-function mutants of the well-known PPGL susceptibility genes SDH and FH, engendered as a result of metabolic imbalances that decrease the activity of histone demethylases (42).”
BackgroundSalminen, A., Kauppinen, A., Hiltunen, M. O., & Kaarniranta, K. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.05.004 · Cited by 145
Morandi, A., Taddei, M. L., Chiarugi, P., & Giannoni, E. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00040 · Cited by 146
“Crucially, SDHx mutations have been associated with EMT in hereditary pheochromocytoma and paraganglioma, as a result of epigenetic alterations (218, 219).”
BackgroundCrona, J., Lamarca, Á., Ghosal, S., Welin, S., Skogseid, B. M., & Pacák, K. (2019) · Endocrine Related Cancer · doi:10.1530/erc-19-0024 · Cited by 140
Turková, H., Prodanov, T., Malý, M., Martucci, V. L., Adams, K. T., Widimsky, J., Jr., Chen, C. C., Ling, A. L., Kebebew, E., Stratakis, C. A., et al. (2015) · Endocrine Practice · doi:10.4158/ep15725.or · Cited by 143
“SDHx syndromes are associated with four different genes that encode subunits A, B, C, and D (5,6).”
BackgroundBuffet, A., Morin, A., Castro‐Vega, L. J., Habarou, F., Lussey‐Lepoutre, C., Letouzé, É., Lefèbvre, H., Guilhem, I., Haissaguerre, M., Raingeard, I., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-2463 · Cited by 137
Self-citationLee, H., Li, C., Ruan, D., He, J., Montal, E. D., Lorenz, S., Girnun, G. D., & Chan, C. (2019) · Nature Communications · doi:10.1038/s41467-019-10374-y · Cited by 142
Cancer metabolism and tumor microenvironment: fostering each other?
Yuan, Y., Li, H., Wang, P., Chen, L., Guo, D. S., Jiang, H., He, B., Qin, S., Wang, K., Li, N., et al. (2021) · Science China Life Sciences · doi:10.1007/s11427-021-1999-2 · Cited by 140
“Epigenetic variations in histones and DNA have been discovered and confirmed as consequences of FH and SDH mutations in tumor specimens harboring FH or SDH mutations (Letouzé et al., 2013).”
BackgroundMitochondria and the hallmarks of cancer
Giampazolias, E., & Tait, S. W. G. (2015) · FEBS Journal · doi:10.1111/febs.13603 · Cited by 144
Advances in histone demethylase KDM4 as cancer therapeutic targets
Lee, D. H., Kim, G. W., Jeon, Y. H., Yoo, J. H., Lee, S. W., & Kwon, S. H. (2020) · The FASEB Journal · doi:10.1096/fj.201902584r · Cited by 137
Richter, S., Peitzsch, M., Rapizzi, E., Lenders, J. W., Qin, N., de Cubas, A. A., Schiavi, F., Rao, J. U., Beuschlein, F., Quinkler, M., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2151 · Cited by 135
Job, S., Drašković, I., Burnichon, N., Buffet, A., Cros, J. F., Lépine, C., Vénisse, A., Robidel, E., Verkarre, V., Méatchi, T., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0139 · Cited by 141
“Here we reinforce this observation and highlight its relevance from the standpoint of diagnosis because even though SDHx/FH-mutated tumors display a hypermethylator phenotype (36), this is the first time that a specific alteration in methylation is associated directly with the metastatic status.”
MethodResultSelf-citationThe α-ketoglutarate dehydrogenase complex in cancer metabolic plasticity
Vatrinet, R., Leone, G., Luise, M. D., Girolimetti, G., Vidone, M., Gasparre, G., & Porcelli, A. M. (2017) · Cancer & Metabolism · doi:10.1186/s40170-017-0165-0 · Cited by 133
Extracellular serine controls epidermal stem cell fate and tumour initiation
Baksh, S. C., Todorova, P. K., Gur-Cohen, S., Hurwitz, B., Ge, Y., Novak, J. S. S., Tierney, M. T., dela Cruz-Racelis, J., Fuchs, E., & Finley, L. W. S. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0525-9 · Cited by 128
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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