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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
Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications
Krueger, F., & Andrews, S. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr167 · Cited by 5,275
Jones, P. A., & Baylin, S. B. (2007) · Cell · doi:10.1016/j.cell.2007.01.029 · Cited by 4,515
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875
CpG island methylator phenotype in colorectal cancer
Toyota, M., Ahuja, N., Ohe-Toyota, M., Herman, J. G., Baylin, S. B., & Issa, J. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.15.8681 · Cited by 2,562
Hypomethylation distinguishes genes of some human cancers from their normal counterparts
Feinberg, A. P., & Vogelstein, B. (1983) · Nature · doi:10.1038/301089a0 · Cited by 2,430
Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma
Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., Pan, F., Pelloski, C. E., Sulman, E. P., Bhat, K. P., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.03.017 · Cited by 2,337
Linking DNA methylation and histone modification: patterns and paradigms
Cedar, H., & Bergman, Y. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2540 · Cited by 2,267 · cited 1×
“As both H3K9 and H3K27 methylation are closely linked with DNA methylation (Cedar and Bergman, 2009), these effects on histone methylation may contribute to the establishment of the hypermethylator phenotype.”
BackgroundMonti, S., Tamayo, P., Mesirov, J., & Golub, T. (2003) · Machine Learning · doi:10.1023/a:1023949509487 · Cited by 2,116
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Items 101–200 of 813
Archier, A., Varoquaux, A. D., Garrigue, P., Montava, M., Guérin, C., Gabriel, S., Beschmout, E., Morange, I., Fakhry, N., Castinetti, F., et al. (2015) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-015-3268-2 · Cited by 126
“The molecular genetics of this metabotype are currently unexplained, but epigenetic mechanisms (histones and methylation modifications) might be involved in addition to genetic mutations [24].”
BackgroundSDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery
Saxena, N., Maio, N., Crooks, D. R., Ricketts, C. J., Yang, Y., Wei, M.-H., Fan, T. W. ‐., Lane, A. N., Sourbier, C., Singh, A., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djv287 · Cited by 125
“Tumors with SDHx mutations have recently been shown to have a global DNA CpG island methylator phenotype (CIMP) attributed to the product-level inhibition of demethylases such as TET2 by elevated succinate (11,12).”
BackgroundMetabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets
Miranda‐Gonçalves, V., Lameirinhas, A., Henrique, R., & Jerónimo, C. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00427 · Cited by 125
Cardio-onco-metabolism: metabolic remodelling in cardiovascular disease and cancer
Karlstaedt, A., Moslehi, J. J., & de Boer, R. A. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00698-6 · Cited by 130
An Epigenetic Role of Mitochondria in Cancer
Liu, Y., Chen, C., Wang, X., Sun, Y., Zhang, J., Chen, J., & Shi, Y. (2022) · Cells · doi:10.3390/cells11162518 · Cited by 131
Succinate: An initiator in tumorigenesis and progression
Zhao, T., Mu, X., & You, Q. (2017) · Oncotarget · doi:10.18632/oncotarget.17734 · Cited by 118
“Recently, succinate was defined as a new “epigenetic hacker” [23, 24] to inhibit DNA and histone demethylases [25, 26], resulting in epigenetic alteration in carcinomas.”
BackgroundGenetic alterations in Krebs cycle and its impact on cancer pathogenesis
Sajnani, K., Islam, F., Smith, R. A., Gopalan, V., & Lam, A. K.-Y. (2017) · Biochimie · doi:10.1016/j.biochi.2017.02.008 · Cited by 121
Roles of mitochondria in the hallmarks of metastasis
Scheid, A. D., Beadnell, T. C., & Welch, D. R. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-01125-8 · Cited by 125
The role of 5-hydroxymethylcytosine in human cancer
Pfeifer, G. P., Xiong, W., Hahn, M. A., & Jin, S. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-1896-7 · Cited by 118
“Similarly, SDH mutations have been linked to a DNA hypermethylation phenotype in paraganglioma (Letouze et al. 2013).”
THERAPY OF ENDOCRINE DISEASE: Treatment of malignant pheochromocytoma and paraganglioma
Baudin, É., Habra, M. A., Deschamps, F., Cote, G. J., Dumont, F., Cabanillas, M. E., Arfi, J., Berdelou, A., Moon, B., Ghuzlan, A. A., et al. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0113 · Cited by 122
Smith, S. C., Sirohi, D., Ohe, C., McHugh, J. B., Hornick, J. L., Kalariya, J. J., Karia, S., Snape, K. M. G., Hodgson, S. V., Cani, A. K., et al. (2017) · Histopathology · doi:10.1111/his.13183 · Cited by 114
“We speculate that these tumours represent yet another example of an emerging phenomenon of phenotypic ‘crossover lesions’ between FH-deficient and SDH-deficient syndromes, analogous to recently described paragangliomas occurring in the setting of germline FH mutation.(35,37,38) Two of these novel cases also raise the…”
BackgroundUpregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells
Shenoy, N., Bhagat, T., Nieves, E., Stenson, M., Lawson, J., Choudhary, G. S., Habermann, T., Nowakowski, G., Singh, R., Wu, X., et al. (2017) · Blood Cancer Journal · doi:10.1038/bcj.2017.65 · Cited by 111
Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer
Huo, M., Zhang, J., Huang, W., & Wang, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.793428 · Cited by 117
Pillai, S., Gopalan, V., Smith, R. A., & Lam, A. K.-Y. (2016) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2016.01.022 · Cited by 113
Porporato, P. E., Payen, V. L., Baselet, B., & Sonveaux, P. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2100-2 · Cited by 115
Evenepoel, L., Papathomas, T. G., Krol, N. M. G., Korpershoek, E., de Krijger, R. R., Persu, A., & Dinjens, W. N. M. (2014) · Genetics in Medicine · doi:10.1038/gim.2014.162 · Cited by 107
Epigenetics and cancer metabolism
Johnson, C., Warmoes, M. O., Shen, X., & Locasale, J. W. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.09.043 · Cited by 113
“This phenotype associated with aggressive clinical behavior of the disease [56].”
BackgroundThe Metabolic Alterations of Cancer Cells
Sciacovelli, M., Gaude, E., Hilvo, M., & Frezza, C. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-416618-9.00001-7 · Cited by 108
Metabolic dysregulation in monogenic disorders and cancer — finding method in madness
Erez, A., & DeBerardinis, R. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3949 · Cited by 105
SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis
Ma, Y., Qi, Y., Wang, L., Zheng, Z., Zhang, Y., & Zheng, J. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.01.030 · Cited by 105
Metabolism and the Epigenome: A Dynamic Relationship
Haws, S. A., Leech, C. M., & Denu, J. M. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.04.002 · Cited by 112
Salminen, A., Haapasalo, A., Kauppinen, A., Kaarniranta, K., Soininen, H. S., & Hiltunen, M. O. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.001 · Cited by 107
“001 increase the global methylation of DNA and histones in tissues (Killian et al., 2013; Letouze et al., 2013; Yang et al., 2013).”
BackgroundInfluentialTCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma
Todisco, S., Convertini, P., Iacobazzi, V., & Infantino, V. (2019) · Cancers · doi:10.3390/cancers12010068 · Cited by 105
Cancer Metabolism: Fueling More than Just Growth
Lee, N., & Kim, D. (2016) · Molecules and Cells · doi:10.14348/molcells.2016.0310 · Cited by 102
“EMT is a developmental process in which epithelial cells lose their epithelial characteristics to become motile mesenchymal stem cells, and cancer cells with epithelial properties can also undergo EMT to become cells with mesenchymal characteristics (Kalluri and Weinberg, 2009).”
BackgroundInfluentialTET-Mediated Hypermethylation Primes SDH-Deficient Cells for HIF2α-Driven Mesenchymal Transition
Morin, A., Goncalves, J., Moog, S., Castro‐Vega, L. J., Job, S., Buffet, A., Fontenille, M., Woszczyk, J., Gimenez‐Roqueplo, A., Letouzé, É., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.022 · Cited by 110
Self-citationFlux balance analysis predicts essential genes in clear cell renal cell carcinoma metabolism
Gatto, F., Miess, H., Schulze, A., & Nielsen, J. (2015) · Scientific Reports · doi:10.1038/srep10738 · Cited by 99
“Indeed, we are interested on whether a feasible region exists upon the constraint imposed by the gene knockout (7), i.”
Multimodal Regulation of Cardiac Myocyte Proliferation
Yuan, X., & Braun, T. W. (2017) · Circulation Research · doi:10.1161/circresaha.117.308428 · Cited by 102
Update of Pheochromocytoma Syndromes: Genetics, Biochemical Evaluation, and Imaging
Alrezk, R., Suárez, A., Tena, I., & Pacák, K. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00515 · Cited by 102
“Subsequent updates showed elevation of NE and the presence of a hypermethylator phenotype similar to SDHxrelated PPGLs (48).”
BackgroundHoekstra, A. S., de Graaff, M. A., Briaire-de Bruijn, I. H., Ras, C., Seifar, R. M., van Minderhout, I., Cornelisse, C. J., Hogendoorn, P. C. W., Breuning, M. H., Suijker, J., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6091 · Cited by 99
“Furthermore, a PGL/PCC cohort showed a hypermethylation phenotype in SDH mutant tumors, reminiscent of the methylation signature of gliomas with IDH mutations [11, 20].”
BackgroundResultInfluentialSalminen, A., Kauppinen, A., & Kaarniranta, K. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1978-z · Cited by 99
“Recent studies have revealed that distinct mutations in the SDH enzyme can provoke the accumulation of succinate and subsequently lead to carcinogenesis, probably due to the inhibition of TET enzymes since SDH mutations are associated with a robust hypermethylation of DNA [38, 39].”
BackgroundGain-of-function mutations in DNMT3A in patients with paraganglioma
Remacha, L., Currás-Freixes, M., Torres-Ruiz, R., Schiavi, F., Torres‐Pérez, R., Calsina, B., Letón, R., Comino‐Méndez, I., Roldán‐Romero, J. M., Montero‐Conde, C., et al. (2018) · Genetics in Medicine · doi:10.1038/s41436-018-0003-y · Cited by 104
Richter, S., Gieldon, L., Pang, Y. K., Peitzsch, M., Huynh, T., Letón, R., Viana, B., Ercolino, T., Mangelis, A., Rapizzi, E., et al. (2018) · Genetics in Medicine · doi:10.1038/s41436-018-0106-5 · Cited by 99
Jia, D., Park, J. H., Kaur, H., Jung, K. H., Yang, S., Tripathi, S., Galbraith, M., Deng, Y., Jolly, M. K., Kaipparettu, B. A., et al. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01385-y · Cited by 97
“Succinate accumulation can cause DNA hypermethylation by inhibiting TET2, and subsequently promotes EMT.(92) Fumarate accumulation inhibits TET-mediated DNA demethylation of the miR-200ba429 locus and, consequently, the repression of ZEB by miR-200 is relieved and EMT is promoted.”
BackgroundThe mitochondrial side of epigenetics
Castegna, A., Iacobazzi, V., & Infantino, V. (2015) · Physiological Genomics · doi:10.1152/physiolgenomics.00096.2014 · Cited by 100
“Screening studies have shown that succinate is a strong inducer of histone and DNA methylation during cancer development (53, 59).”
BackgroundMetastatic Pheochromocytomas and Abdominal Paragangliomas
Granberg, D. O., Juhlin, C. C., & Falhammar, H. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa982 · Cited by 96
“As TET enzymes play a central role in DNA demethylation processes, the diminished enzymatic activity would in theory help to upkeep tumor DNA hypermethylation.”
BackgroundHypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors: Targeting Genetically Driven Tumor Hypoxia
Toledo, R. A., Jiménez, C., Armaiz-Peña, G., Arenillas, C., Capdevila, J., & Dahia, P. L. M. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnac025 · Cited by 103
Salminen, A., Kaarniranta, K., Hiltunen, M. O., & Kauppinen, A. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.03.030 · Cited by 97
5-Hydroxymethylcytosine: An epigenetic mark frequently deregulated in cancer
Kroeze, L. I., van der Reijden, B. A., & Jansen, J. H. (2015) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2015.01.001 · Cited by 97
Biological significance of the CpG island methylator phenotype
Suzuki, H., Yamamoto, E., Maruyama, R., Niinuma, T., & Kai, M. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.07.007 · Cited by 99
“Moreover, in recent years technological advances have enabled genome-wide DNA methylation analysis, and unsupervised clustering of the methylome data has clearly delineated CIMP-positive groups in breast [20], lung [21], colorectal [22], endometrial [23], bladder [24] oral [25] and renal cancer [26], as well as in gli…”
BackgroundThe multifaceted contribution of α-ketoglutarate to tumor progression: An opportunity to exploit?
Abla, H., Sollazzo, M., Gasparre, G., Iommarini, L., & Porcelli, A. M. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.031 · Cited by 99
“Being structural analogues of αKG, both enantiomers are weak competitive inhibitors of OGDD occupying the enzyme’s catalytic site, with different levels of potency [72] (Fig.”
BackgroundInfluentialModulation of dysregulated cancer metabolism by plant secondary metabolites: A mechanistic review
Fakhri, S., Moradi, S. Z., Farzaei, M. H., & Bishayee, A. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.02.007 · Cited by 97
Malignant pheochromocytoma–paraganglioma: pathogenesis, TNM staging, and current clinical trials
Román-Gonzaléz, A., & Jiménez, C. (2017) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000330 · Cited by 95
The TCA cycle as a bridge between oncometabolism and DNA transactions in cancer
Ciccarone, F., Vegliante, R., Leo, L. D., & Ciriolo, M. R. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.06.008 · Cited by 97
Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans
Kaasinen, E., Kuismin, O., Rajamäki, K., Ristolainen, H., Aavikko, M., Kondelin, J., Saarinen, S., Berta, D. G., Katainen, R., Hirvonen, E. A. M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09198-7 · Cited by 92
Lin, E. P., Chin, B. B., Fishbein, L. M., Moritani, T., Montoya, S. P., Ellika, S., & Newlands, S. D. (2022) · Radiology Imaging Cancer · doi:10.1148/rycan.210088 · Cited by 95
Clinical significance of T cell metabolic reprogramming in cancer
Herbel, C., Patsoukis, N., Bardhan, K., Seth, P., Weaver, J. D., & Boussiotis, V. A. (2016) · Clinical and Translational Medicine · doi:10.1186/s40169-016-0110-9 · Cited by 99
“Such alterations have been shown to be sufficient to drive oncogenesis [114, 115].”
BackgroundEpigenetic regulators in cancer therapy and progression
Marei, H. E. S. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-01003-7 · Cited by 116
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BackgroundRecurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas
Remacha, L., Pirman, D. A., Mahoney, C. E., Coloma, J., Calsina, B., Currás-Freixes, M., Letón, R., Torres‐Pérez, R., Richter, S., Pita, G., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.02.017 · Cited by 88
Succinate Receptor 1: An Emerging Regulator of Myeloid Cell Function in Inflammation
Krzak, G., Willis, C. M., Smith, J. A., Pluchino, S., & Peruzzotti‐Jametti, L. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.11.004 · Cited by 91
“Finally, succinate accumulation also results in epigenetic reprograming by inhibiting tet methylcytosine dioxygenase 2 (TET2) and Jumonji c domain-containing (JMJD) protein families, leading to histone and DNA methylation [65].”
BackgroundSDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex
Tête, A., Debizet, K., Imler, J., Tomkiewicz, C., Blanc, É., Barouki, R., Coumoul, X., & Bortoli, S. (2023) · Environment International · doi:10.1016/j.envint.2023.108219 · Cited by 95
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Guitart, A. V., Panagopoulou, T. I., Villacreces, A., Vukovic, M., Sepulveda, C., Allen, L., Carter, R. N., van de Lagemaat, L. N., Morgan, M., Giles, P., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20161087 · Cited by 86
“…Phd2 (Hewitson et al., 2007), the Tet enzymes, and KDMs (Xiao et al., 2012), and as a consequence, tumor cells with FH mutations have increased HIF-1α stability and display a hypermethylator phenotype (Isaacs et al., 2005; Pollard et al., 2007; Letouzé et al., 2013; Castro-Vega et al., 2014).”
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“, IDH1 [80], SDH [81], TET2 [69]), which lead to uncontrolled division and growth of cells [82].”
BackgroundBénit, P., Letouzé, É., Rak, M., Aubry, L., Burnichon, N., Favier, J., Gimenez‐Roqueplo, A., & Rustin, P. (2014) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2014.03.013 · Cited by 89
Self-citationReprogramming of central carbon metabolism in cancer stem cells
Wong, T. L., Che, N., & Ma, S. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.05.012 · Cited by 86
Eisenhofer, G., Klink, B., Richter, S., Lenders, J. W. M., & Robledo, M. (2017) · Europe PMC (PubMed Central) · Cited by 84
Succinate: A New Epigenetic Hacker
Yang, M. H., & Pollard, P. J. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.05.015 · Cited by 86
“Integration of methylation and gene expression data revealed, whereas most hypermethylated CpG sites had no functional consequences, there were 191 genes that showed correlated levels of hypermethylation and downregulation (Letouzé et al., 2013).”
BackgroundResultInfluentialO’Toole, S. M., Dénes, J., Robledo, M., Stratakis, C. A., & Korbonits, M. (2015) · Endocrine Related Cancer · doi:10.1530/erc-15-0241 · Cited by 83
“2007) resulting in potential epigenetic modification (Letouzé et al. 2013).”
BackgroundNarne, P., Pandey, V., & Phanithi, P. B. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.05.008 · Cited by 84
Aim, L. B., Pigny, P., Castro‐Vega, L. J., Buffet, A., Amar, L., Bertherat, J. Y., Drui, D., Guilhem, I., Baudin, É., Lussey‐Lepoutre, C., et al. (2019) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2018-105714 · Cited by 83
Self-citationMitochondrial Metabolism in Carcinogenesis and Cancer Therapy
Moindjie, H., Rodrigues, S., & Nahmias, C. (2021) · Cancers · doi:10.3390/cancers13133311 · Cited by 88
Qin, N., de Cubas, A. A., García-Martín, R., Richter, S., Peitzsch, M., Menschikowski, M., Lenders, J. W. M., Timmers, H. J. L. M., Mannelli, M., Opocher, G., et al. (2014) · International Journal of Cancer · doi:10.1002/ijc.28868 · Cited by 88
The genomic landscape of phaeochromocytoma
Flynn, A., Benn, D. E., Clifton-Bligh, R. J., Robinson, B. G., Trainer, A. H., James, P. A., Hogg, A., Waldeck, K., George, J., Li, J., et al. (2014) · The Journal of Pathology · doi:10.1002/path.4503 · Cited by 81
“These observations are consistent with the dysregulation of DNA and histone modifiers by succinate-dependent inhibition in SDH-mutant PCC/PGL tumours [74,75].”
BackgroundLiaghat, M., Ferdousmakan, S., Mortazavi, S. H., Yahyazadeh, S., Irani, A., Banihashemi, S., Asl, F. S. S., Akbari, A., Farzam, F., Aziziyan, F., et al. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01957-4 · Cited by 87
Emerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy
Zhu, Y., Dean, A. E., Horikoshi, N., Heer, C. D., Spitz, D. R., & Gius, D. R. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120844 · Cited by 82
Gudgeon, N. H., Munford, H., Bishop, E. L., Hill, J., Fulton-Ward, T., Bending, D., Roberts, J., Tennant, D. A., & Dimeloe, S. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111193 · Cited by 85
Clinical implications of the oncometabolite succinate in SDHx ‐mutation carriers
Eijkelenkamp, K., Osinga, T. E., Links, T. P., & van der Horst‐Schrivers, A. N. A. (2019) · Clinical Genetics · doi:10.1111/cge.13553 · Cited by 78
“They identified 191 genes showing significant hypermethylation, due to an inhibition of DNA demethylation, and downregulation in SDHx-related PGL/PCC.(84) The most significant epigenetically silenced genes were those encoding phenyl-ethanolamineN-methyltransferase (PNMT) and keratine 19 (KRT19), which are involved in…”
BackgroundInfluentialCurrás-Freixes, M., Piñeiro-Yáñez, E., Montero‐Conde, C., Apellániz-Ruiz, M., Calsina, B., Mančíková, V., Remacha, L., Richter, S., Ercolino, T., Rogowski-Lehmann, N., et al. (2017) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2017.04.009 · Cited by 78
Metabolic control of the epigenome in systemic Lupus erythematosus
Oaks, Z., & Perl, A. (2014) · Autoimmunity · doi:10.3109/08916934.2013.834495 · Cited by 76
“Succinate is a product of TET and JmjC demethylation, which acts through feedback inhibition to block further DNA and histone demethylation [75].”
BackgroundRistić, B., Bhutia, Y. D., & Ganapathy, V. (2017) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2017.05.003 · Cited by 75
“The relevance of succinate to carcinogenesis and tumor growth came to the forefront in the field of cancer biology with the observations that loss-of-function mutations in succinate dehydrogenase (SDH) are sufficient to drive certain cancers such as paraganglioma, renal cell carcinoma, and gastrointestinal stromal tum…”
BackgroundMetabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond
Teoh, S. T., & Lunt, S. Y. (2017) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1406 · Cited by 77
“For example, both chromosomal hypomethylation and hypermethylation, leading to aberrant transcriptional activation and silencing, respectively, may promote metastasis under different conditions.(136,151) Some of this heterogeneity may be attributed to tissue of origin, such as the specific association of sarcosine wit…”
BackgroundSulfur metabolism and its contribution to malignancy
Ward, N. P., & DeNicola, G. M. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.05.001 · Cited by 74
Metabolic Mechanisms of Epigenetic Regulation
Meier, J. L. (2013) · ACS Chemical Biology · doi:10.1021/cb400689r · Cited by 75
Koivunen, P., & Laukka, T. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2721-8 · Cited by 76
“1 3 hypothesize that, in addition to downregulation of TETs, inhibition of the catalytic activity of TETs by these compounds could be responsible for the low 5hmC levels and EMT in cancers with IDH1 or 2, FH or SDH loss-of-function mutations [53, 55, 58].”
BackgroundNeumann, H. P. H., Young, W. F., Krauß, T., Bayley, J., Schiavi, F., Opocher, G., Boedeker, C. C., Tirosh, A., Castinetti, F., Ruf, J., et al. (2018) · Endocrine Related Cancer · doi:10.1530/erc-18-0085 · Cited by 73
The Tricarboxylic Acid Cycle at the Crossroad Between Cancer and Immunity
Scagliola, A., Mainini, F., & Cardaci, S. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7974 · Cited by 75
Gupta, G., & Pacák, K. (2017) · Endocrine Practice · doi:10.4158/ep161718.ra · Cited by 77
“The association between mutations in the FH gene and PPGLs was first identified in 2013, after which more gene analysis studies were performed and reported germline FH mutations in a total of eight cases worldwide (62,71,78).”
BackgroundInfluentialAlternative assembly of respiratory complex II connects energy stress to metabolic checkpoints
Bezawork‐Geleta, A., Wen, H., Dong, L., Yan, B., Vider, J., Boukalová, Š., Krobova, L., Vanova, K. H., Zobalová, R., Sobol, M. A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04603-z · Cited by 73
Røsland, G. V., Dyrstad, S. E., Tusubira, D., Helwa, R., Tan, T. Z., Lotsberg, M. L., Pettersen, I. K. N., Berg, A., Kindt, C. K., Hoel, F., et al. (2019) · Cancer & Metabolism · doi:10.1186/s40170-019-0197-8 · Cited by 69
A Systems Approach to Predict Oncometabolites via Context-Specific Genome-Scale Metabolic Networks
Nam, H., Campodonico, M. A., Bordbar, A., Hyduke, D. R., Kim, S., Zielinski, D. C., & Palsson, B. Ø. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003837 · Cited by 71
Chemical signaling between gut microbiota and host chromatin: What is your gut really saying?
Krautkramer, K. A., Rey, F. E., & Denu, J. M. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r116.761577 · Cited by 70
Cleven, A. H. G., Suijker, J., Agrogiannis, G., Bruijn, I. H. B., Frizzell, N., Hoekstra, A. S., Wijers‐Koster, P. M., Cleton-Jansen, A., & Bovée, J. V. M. G. (2017) · Clinical Sarcoma Research · doi:10.1186/s13569-017-0074-6 · Cited by 72
Calsina, B., Castro‐Vega, L. J., Torres‐Pérez, R., Inglada‐Pérez, L., Currás-Freixes, M., Roldán‐Romero, J. M., Mančíková, V., Letón, R., Remacha, L., Santos, M., et al. (2019) · Theranostics · doi:10.7150/thno.35458 · Cited by 70
“For the preparation of conditioned media (CM), wild type and Sdhb-/- immortalized mouse chromaffin cells (imCCs) [29] were seeded under standard culture conditions (DMEM/Glutamax, 10% FBS and 1% penicillin-streptomycin) and maintained at 5% CO2/37°C.”
BackgroundMethodSelf-citationPamporaki, C., Berends, A. M. A., Filippatos, A., Prodanov, T., Meuter, L., Prejbisz, A., Beuschlein, F., Faßnacht, M., Timmers, H. J. L. M., Nölting, S., et al. (2023) · The Lancet Digital Health · doi:10.1016/s2589-7500(23)00094-8 · Cited by 70
Targeting cancer metabolic pathways for improving chemotherapy and immunotherapy
Luo, Z., Eichinger, K. M., Zhang, A., & Li, S. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216396 · Cited by 71
de Cubas, A. A., Korpershoek, E., Inglada‐Pérez, L., Letouzé, É., Currás-Freixes, M., Fernández, A. F., Comino‐Méndez, I., Schiavi, F., Mančíková, V., Eisenhofer, G., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2804 · Cited by 73
“SDHBPPGLs have recently shown to have a CpG island hypermethylator phenotype (high-CIMP) with a previously defined signature of 298 hypermethylatedCpGs (2).”
InfluentialSelf-citationPheochromocytoma and Paraganglioma
Pacák, K., & Wimalawansa, S. J. (2015) · Endocrine Practice · doi:10.4158/ep14481.ra · Cited by 71
Deciphering the molecular basis of invasiveness in Sdhb -deficient cells
Loriot, C., Domingues, M. J., Berger, A., Menara, M., Ruel, M., Morin, A., Castro‐Vega, L. J., Letouzé, É., Martinelli, C., Bemelmans, A., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5106 · Cited by 69
“Experiments were performed using one of the two imCC clones: clone 8 and its WT counterpart [24].”
BackgroundMethodInfluentialSelf-citationImpériale, A., Moussallieh, F., Roche, P., Battini, S., Çiçek, A. E., Sebag, F. A., Brunaud, L., Barlier, A., Elbayed, K., Loundou, A., et al. (2015) · Neoplasia · doi:10.1016/j.neo.2014.10.010 · Cited by 69
“Recently, it has been shown that SDHx-related tumors exhibited a hypermethylated phenotype [25].”
BackgroundLussey‐Lepoutre, C., Bellucci, A., Morin, A., Buffet, A., Amar, L., Janin, M., Ottolenghi, C., Zinzindohoué, F., Autret, G., Burnichon, N., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1576 · Cited by 76
“The tumors grew in 100% of mice and tumors were macroscopically visible after 2 weeks for WT and 1 month for Sdhb / tumors, in line with the reduced growth rate of Sdhb / cells observed in vitro (13).”
BackgroundMethodInfluentialSelf-citationCarney triad can be (rarely) associated with germline succinate dehydrogenase defects
Boikos, S. A., Xekouki, P., Fumagalli, E. R., Faucz, F. R., Raygada, M. J., Szarek, E., Ball, E. R., Kim, S., Miettinen, M., Helman, L. J., et al. (2015) · European Journal of Human Genetics · doi:10.1038/ejhg.2015.142 · Cited by 68
Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate
Goncalves, J., Moog, S., Morin, A., Gentric, G., Müller, S., Morrell, A. P., Kľučková, K., Stewart, T. J., Andoniadou, C. L., Lussey‐Lepoutre, C., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2936 · Cited by 77
“This was unexpected as previous transcriptome analyses of human tumor samples have classified all SDHx-mutated tumors together with VHL-mutated ones in a “pseudohypoxic” cluster (16, 17).”
BackgroundMethodInfluentialSelf-citationMetabolic switches during development and regeneration
Mahmoud, A. I. (2023) · Development · doi:10.1242/dev.202008 · Cited by 65
Yang, S., Zhan, Q., Su, D., Cui, X., Zhao, J., Wang, Q., Hong, B., Ju, J., Cheng, C., Yang, E., et al. (2024) · Neuro-Oncology · doi:10.1093/neuonc/noae040 · Cited by 69
Lee, S. Y., Ju, M. K., Jeon, H. M., Lee, Y. J., Kim, C. H., Park, H. G., Han, S. I., & Kang, H. S. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/1027453 · Cited by 69
Mito-Nuclear Communication by Mitochondrial Metabolites and Its Regulation by B-Vitamins
Janssen, J. J. E., Grefte, S., Keijer, J., & de Boer, V. C. J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00078 · Cited by 70
“Succinate-induced inhibition of KDMs and TETs was shown to initiate histone and DNA hypermethylation, which had large effects on the expression of genes that regulate cancer cell progression (Cervera et al., 2009; Killian et al., 2013; Letouze et al., 2013; Mason and Hornick, 2013) and the induction of epithelial-to-m…”
BackgroundMetabolic implications of hypoxia and pseudohypoxia in pheochromocytoma and paraganglioma
Kľučková, K., & Tennant, D. A. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2801-6 · Cited by 68
“…inactivation may be more complete in SDHBmutated tumours vs. tumours with mutations in other SDH subunits resulting in a stronger inhibition of 2-OGdependent demethylation due to higher succinate levels, but the authors were unable to confirm this hypothesis experimentally (Letouze et al. 2013).”
BackgroundResultInfluential15 YEARS OF PARAGANGLIOMA: Pathology of pheochromocytoma and paraganglioma
Tischler, A. S., & de Krijger, R. R. (2015) · Endocrine Related Cancer · doi:10.1530/erc-15-0261 · Cited by 66
Challenges in Paragangliomas and Pheochromocytomas: from Histology to Molecular Immunohistochemistry
Juhlin, C. C. (2021) · Endocrine Pathology · doi:10.1007/s12022-021-09675-0 · Cited by 69
“One important group of inhibited enzymes are the Ten-eleven translocation (TET) proteins responsible for genomic demethylation [49, 51, 52].”
BackgroundZethoven, M., Martelotto, L. G., Pattison, A., Bowen, B., Balachander, S., Flynn, A., Rossello, F. J., Hogg, A., Miller, J. A., Fryšák, Z., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34011-3 · Cited by 67
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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