The Emerging Role of Succinate Dehyrogenase Genes (SDHx) in Tumorigenesis
Abstract
Transformation of a normal cell to cancerous one is dependent on the accumulation of several genetic and epigenetic alterations. One of the candidate driver genetic alterations can happen in succinate dehydrogenases (SDHx) coding gene include SDHA, SDHB, SDHC, SDHD, and SDHAF2. The most important SDH mutation is in the SDHD gene, which encodes the smallest subunit of mitochondrial complex II (SDH). It has key function both in familial and non-familial hereditary paraganglioma/phaeochromocytoma syndrome (HPGL/PCC). SDHx genes mutations can have resulted in genetic and epigenetic changes like histone hypermethylation. These properties can lead to succinate-mediated inhibition of α-ketoglutarate-dependent dioxygenases. So hypoxic conditions can generate subsequent neoplastic transformation, and in this review, we are presenting the role of SDHx in several malignancies.
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2. Ashkenazi R, Gentry SN, Jackson TL. Pathways to Tumorigenesis—Modeling Mutation Acquisition in Stem Cells and Their Progeny. Neoplasia. 2008;10(11):1170-82.
3. Barrett JC. Mechanisms of multistep carcinogenesis and carcinogen risk assessment. Environ Health Perspect. 1993; 100:9-20.
4. Sarmadi S, Izadi-Mood N, Sotoudeh K, et al. Altered PTEN expression; a diagnostic marker for differentiating normal, hyperplastic and neoplastic endometrium. Diagn Pathol. 2009; 4:41.
5. Mohammadi-asl J, Larijani B, Khorgami Z, et al. Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARβ2 genes in papillary thyroid carcinoma. Med Oncol. 2011;28(4):1123-8.
6. Natanzi MM, Pasalar P, Kamalinejad M, et al. Effect of aqueous extract of Elaeagnus angustifolia fruit on experimental cutaneous wound healing in rats. Acta Med Iran. 2012;50(9):589-96.
7. Haghpanah V, Shooshtarizadeh P, Heshmat R, et al. Immunohistochemical analysis of survivin expression in thyroid follicular adenoma and carcinoma. Appl Immunohistochem Mol Morphol. 2006; 14(4):422-5.
8. Omidfar K, Moinfar Z, Sohi AN, et al. Expression of EGFRvIII in thyroid carcinoma: immunohistochemical study by camel antibodies. Immunol Invest. 2009; 38(2):165-80.
9. Kim HJ, Winge DR. Emerging concepts in the flavinylation of succinate dehydrogenase. Biochim Biophys Acta. 2013; 1827(5):627-36.
10. Yang M, Pollard PJ. Succinate: a new epigenetic hacker. Cancer Cell. 2013;23(6):709-11.
11. Xiao M, Yang H, Xu W, et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012; 26(12):1326-38.
12. Bardella C, Pollard PJ, Tomlinson I. SDH mutations in cancer. Biochim Biophys Acta. 2011; 1807(11):1432-43.
13. Clark GR, Sciacovelli M, Gaude E, et al. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab. 2014; 99(10):E2046-50
14. Miettinen M, Sarlomo-Rikala M, McCue P, et al. Mapping of succinate dehydrogenase losses in 2258 epithelial neoplasms. Appl Immunohistochem Mol Morphol. 2014; 22(1):31-6.
15. Pollard PJ, Brière JJ, Alam NA, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005; 14(15):2231-9.
16. Letouzé E, Martinelli C, Loriot C, et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 2013;23(6):739-52.
17. Joensuu H, Hohenberger P, Corless CL. Gastrointestinal stromal tumour. The Lancet. 2013; 382(9896):973-983.
18. Corless CL. Gastrointestinal stromal tumors: what do we know now? Mod Pathol. 2014; 27 Suppl 1:S1-16.
19. Janeway KA, Kim SY, Lodish M, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 2011; 108(1):314-8.
20. Gill AJ, Hes O, Papathomas T, et al. Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. Am J Surg Pathol. 2014; 38(12):1588-602.
21. Dwight T, Benn DE, Clarkson A, et al. Loss of SDHA expression identifies SDHA mutations in succinate dehydrogenase–deficient gastrointestinal stromal tumors. Am J Surg Pathol. 2013; 37(2):226-33.
22. Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012; 12(10): 685–698.
23. Burnichon N, Brière JJ, Libé R, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010; 19(15):3011-20
24. Evenepoel L, Papathomas TG, Krol N, et al. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 2015; 17(8):610-20.
25. Alimoghaddam K, Shariftabrizi A, Tavangar M, et al. Anti-leukemic and anti-angiogenesis efficacy of arsenic trioxide in new cases of acute promyelocytic leukemia. Leuk Lymphoma. 2006; 47(1):81-8.
26. Gaude E, Frezza C. Defects in mitochondrial metabolism and cancer. Cancer Metab. 2014; 2: 10.
27. Wentzel JF, Lewies A, Bronkhorst AJ, et al. Exposure to high levels of fumarate and succinate leads to apoptotic cytotoxicity and altered global DNA methylation profiles in vitro. Biochimie. 2017; 135: 28-34.
28. Hensen EF, Bayley JP. Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma. Fam Cancer. 2011; 10(2):355-63.
29. Bayley JP, Devilee P, Taschner PE. The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency. BMC Med Genet. 2005; 6: 39.
30. Xekouki P, Pacak K, Almeida M, et al. Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: a new association for SDH? J Clin Endocrinol Metab. 2012; 97(3):E357-66.
31. Li L, Eid JE, Paz AC, et al. Metabolic Enzymes in Sarcomagenesis: Progress Toward Biology and Therapy. BioDrugs. 2017; 31(5):379-392.
32. Yang M, Soga T, Pollard PJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013; 123(9):3652-8.
33. Dahia PLM, Ross KN, Wright ME, et al. A HIF1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 2005; 1(1): e8.
34. Gill AJ, Benn DE, Chou A, et al. Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2010; 41(6):805-14.
35. Santi R, Rapizzi E, Canu L, et al. Potential Pitfalls of SDH Immunohistochemical Detection in Paragangliomas and Phaeochromocytomas Harbouring Germline SDHx Gene Mutation. Anticancer Res. 2017; 37(2):805-812.
36. King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006;25(34):4675-82.
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| Files | ||
| Issue | Vol 13, No 2 (2019) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v13i2.692 | |
| Keywords | ||
| Succinate dehydrogenases, Tumor, Genetic | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Nazar E, Khatami F, Saffar H, Tavangar SM. The Emerging Role of Succinate Dehyrogenase Genes (SDHx) in Tumorigenesis. Int J Hematol Oncol Stem Cell Res. 2019;13(2):72-82.
