Cited by 813Adrenal and Paraganglionic TumorsChromatin Remodeling and CancerNeurofibromatosis and Schwannoma Cases

SDH mutations establish a hypermethylator phenotype in paraganglioma

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Letouzé, Eric, Martinelli, Cosimo, Loriot, Céline, Burnichon, Nelly, Abermil, Nasséra, Ottolenghi, Chris, Janin, Maxime, Menara, Mélanie +10 more·2013·Cancer Cell

Abstract

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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Crossref · 10.1016/j.ccr.2013.04.018

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  • Fumarate and succinate accumulation can inhibit some alpha-ketoglutarate-dependent dioxygenases, resulting in hypermethylation of DNA and histones in tumors with FH or SDH loss.

    “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

  • Mutations in succinate dehydrogenase subunit B (SDHB) cause susceptibility to familial pheochromocytoma, familial paraganglioma, and gastrointestinal stromal tumors.

    “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]

  • Succinate accumulation via inhibition of 2-OGDD causes epigenetic modification and transformation to a hypermethylated phenotype.

    “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]

  • R-2-HG, succinate, and fumarate are recognized as oncometabolites based on ample experimental data.

    “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]

  • SDH-deficient cells exhibit increased tumorigenesis, reversed by α-KG, supporting that succinate accumulation contributes to tumorigenesis through epigenetic modification.

    “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]

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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
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2013-06
Volume
23
Issue
6
Pages
739-752
ISSN
1535-6108 (ISSN-L)
OpenAlex
W2061662711
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
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 › 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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