Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Rare insights into cancer biology

Oncogene volume 33, pages 2547–2556 (2014)Cite this article

Subjects

Abstract

Cancer-associated mutations have been identified in the metabolic genes succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH), advancing and challenging our understanding of cellular function and disease mechanisms and providing direct links between dysregulated metabolism and cancer. Some striking parallels exist in the cellular consequences of the genetic mutations within this triad of cancer syndromes, including accumulation of oncometabolites and competitive inhibition of 2-oxoglutarate-dependent dioxygenases, particularly, hypoxia-inducible factor (HIF) prolyl hydroxylases, JmjC domain-containing histone demethylases (part of the JMJD family) and the ten-eleven translocation (TET) family of 5methyl cytosine (5mC) DNA hydroxylases. These lead to activation of HIF-dependent oncogenic pathways and inhibition of histone and DNA demethylation. Mutations in FH, resulting in loss of enzyme activity, predispose affected individuals to a rare cancer, hereditary leiomyomatosis and renal cell cancer (HLRCC), characterised by benign smooth muscle cutaneous and uterine tumours (leiomyomata) and an aggressive form of collecting duct and type 2 papillary renal cancer. Interestingly, loss of FH activity results in the accumulation of high levels of fumarate that can lead to the non-enzymatic modification of cysteine residues in multiple proteins (succination) and in some cases to their disrupted function. Here we consider that the study of rare diseases such as HLRCC, combining analyses of human tumours and cell lines with in vitro and in vivo murine models has provided novel insights into cancer biology associated with dysregulated metabolism and represents a useful paradigm for cancer research.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Warburg O . On respiratory impairment in cancer cells. Science 1956; 124: 269–270.

    Article  CAS  PubMed  Google Scholar 

  2. Warburg O . On the origin of cancer cells. Science 1956; 123: 309–314.

    Article  CAS  PubMed  Google Scholar 

  3. Vander Heiden MG, Cantley LC, Thompson CB . Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029–1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Maher EA, Marin-Valencia I, Bachoo RM, Mashimo T, Raisanen J, Hatanpaa KJ et al. Metabolism of [U-13 C]glucose in human brain tumors in vivo. NMR Biomed 2012; 25: 1234–1244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ashcroft FM, Rorsman P . Diabetes mellitus and the beta cell: the last ten years. Cell 2012; 148: 1160–1171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Semenza GL . Oxygen sensing, homeostasis, and disease. N Engl J Med 2011; 365: 537–547.

    Article  CAS  PubMed  Google Scholar 

  7. Kaelin WG Jr, Ratcliffe PJ . Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 2008; 30: 393–402.

    Article  CAS  PubMed  Google Scholar 

  8. DeBerardinis RJ, Thompson CB . Cellular metabolism and disease: what do metabolic outliers teach us? Cell 2012; 148: 1132–1144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  PubMed  Google Scholar 

  10. Schulze A, Harris AL . How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 2012; 491: 364–373.

    Article  CAS  PubMed  Google Scholar 

  11. Thompson CB . Metabolic enzymes as oncogenes or tumor suppressors. N Engl J Med 2009; 360: 813–815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Frezza C, Pollard PJ, Gottlieb E . Inborn and acquired metabolic defects in cancer. J Mol Med (Berl) 2011; 89: 213–220.

    Article  CAS  Google Scholar 

  13. Tomita M, Kami K . Cancer. Systems biology, metabolomics, and cancer metabolism. Science 2012; 336: 990–991.

    Article  CAS  PubMed  Google Scholar 

  14. Glunde K, Bhujwalla ZM, Ronen SM . Choline metabolism in malignant transformation. Nat Rev Cancer 2011; 11: 835–848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Choi C, Ganji SK, DeBerardinis RJ, Hatanpaa KJ, Rakheja D, Kovacs Z et al. 2-Hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 2012; 18: 624–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Choi C, Ganji SK, DeBerardinis RJ, Dimitrov IE, Pascual JM, Bachoo R et al. Measurement of glycine in the human brain in vivo by 1H-MRS at 3 T: application in brain tumors. Magn Reson Med 2011; 66: 609–618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pollard PJ, Spencer-Dene B, Shukla D, Howarth K, Nye E, El-Bahrawy M et al. Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer Cell 2007; 11: 311–319.

    Article  CAS  PubMed  Google Scholar 

  18. Yang Y, Valera VA, Padilla-Nash HM, Sourbier C, Vocke CD, Vira MA et al. UOK 262 cell line, fumarate hydratase deficient (FH-/FH-) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic pathway in human cancer. Cancer Genet Cytogenet 2010; 196: 45–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bayley JP, van Minderhout I, Hogendoorn PC, Cornelisse CJ, van der Wal A, Prins FA et al. Sdhd and SDHD/H19 knockout mice do not develop paraganglioma or pheochromocytoma. PLoS One 2009; 4: e7987.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Piruat JI, Pintado CO, Ortega-Saenz P, Roche M, Lopez-Barneo J . The mitochondrial SDHD gene is required for early embryogenesis, and its partial deficiency results in persistent carotid body glomus cell activation with full responsiveness to hypoxia. Mol Cell Biol 2004; 24: 10933–10940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang Y, Valera V, Sourbier C, Vocke CD, Wei M, Pike L et al. A novel fumarate hydratase-deficient HLRCC kidney cancer cell line, UOK268: a model of the Warburg effect in cancer. Cancer Genet 2012; 205: 377–390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. MacKenzie ED, Selak MA, Tennant DA, Payne LJ, Crosby S, Frederiksen CM et al. Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol 2007; 27: 3282–3289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005; 8: 143–153.

    Article  CAS  PubMed  Google Scholar 

  24. Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brustle A et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 2012; 488: 656–659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, Chio II et al. D-2-Hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev 2012; 26: 2038–2049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ternette N, Yang M, Laroyia M, Kitagawa M, O’Flaherty L, Wolhulter K et al. Inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency. Cell Rep 2013; 3: 689–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 2011; 20: 524–537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Soga T, Igarashi K, Ito C, Mizobuchi K, Zimmermann HP, Tomita M . Metabolomic profiling of anionic metabolites by capillary electrophoresis mass spectrometry. Anal Chem 2009; 81: 6165–6174.

    Article  CAS  PubMed  Google Scholar 

  29. Soga T, Baran R, Suematsu M, Ueno Y, Ikeda S, Sakurakawa T et al. Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. J Biol Chem 2006; 281: 16768–16776.

    Article  CAS  PubMed  Google Scholar 

  30. Soga T, Ohashi Y, Ueno Y, Naraoka H, Tomita M, Nishioka T . Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. J Proteome Res 2003; 2: 488–494.

    Article  CAS  PubMed  Google Scholar 

  31. Stratton MR . Journeys into the genome of cancer cells. EMBO Mol Med 2013; 5: 169–172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bayley JP, Devilee P . Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes barking up the right tree? Curr Opin Genet Dev 2010; 20: 324–329.

    Article  CAS  PubMed  Google Scholar 

  33. Knudson AG Jr . Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68: 820–823.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gottlieb E, Tomlinson IP . Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 2005; 5: 857–866.

    Article  CAS  PubMed  Google Scholar 

  35. Ward PS, Thompson CB . Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 2012; 21: 297–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Salway JG . Metabolism at a Glance (At a Glance (Blackwell)). Blackwell Publishers, Oxford, UK, 1999.

    Google Scholar 

  37. Bardella C, Pollard PJ, Tomlinson I . SDH mutations in cancer. Biochim Biophys Acta 2011; 1807: 1432–1443.

    Article  CAS  PubMed  Google Scholar 

  38. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000; 287: 848–851.

    Article  CAS  PubMed  Google Scholar 

  39. Lenders JW, Eisenhofer G, Mannelli M, Pacak K . Phaeochromocytoma. Lancet 2005; 366: 665–675.

    Article  PubMed  Google Scholar 

  40. Vanharanta S, Buchta M, McWhinney SR, Virta SK, Peczkowska M, Morrison CD et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet 2004; 74: 153–159.

    Article  CAS  PubMed  Google Scholar 

  41. Burnichon N, Briere JJ, Libe R, Vescovo L, Riviere J, Tissier F et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 2010; 19: 3011–3020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 2009; 325: 1139–1142.

    Article  CAS  PubMed  Google Scholar 

  43. Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001; 69: 49–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Niemann S, Muller U . Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000; 26: 268–270.

    Article  CAS  PubMed  Google Scholar 

  45. Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 2008; 100: 1260–1262.

    Article  CAS  PubMed  Google Scholar 

  46. Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA 2011; 108: 314–318.

    Article  CAS  PubMed  Google Scholar 

  47. Pasini B, Stratakis CA . SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. J Intern Med 2009; 266: 19–42.

    Article  CAS  PubMed  Google Scholar 

  48. Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 2003; 63: 5615–5621.

    CAS  PubMed  Google Scholar 

  49. Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab 2007; 92: 3822–3828.

    Article  CAS  PubMed  Google Scholar 

  50. Young RM, Simon MC . Untuning the tumor metabolic machine: HIF-alpha: pro- and antitumorigenic? Nat Med 2012; 18: 1024–1025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005; 14: 2231–2239.

    Article  CAS  PubMed  Google Scholar 

  52. Briere JJ, Favier J, Benit P, El Ghouzzi V, Lorenzato A, Rabier D et al. Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions. Hum Mol Genet 2005; 14: 3263–3269.

    Article  CAS  PubMed  Google Scholar 

  53. Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005; 7: 77–85.

    Article  CAS  PubMed  Google Scholar 

  54. Dahia PL . Transcription association of VHL and SDH mutations link hypoxia and oxidoreductase signals in pheochromocytomas. Ann N Y Acad Sci 2006; 1073: 208–220.

    Article  CAS  PubMed  Google Scholar 

  55. Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M et al. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 2005; 1: 72–80.

    Article  CAS  PubMed  Google Scholar 

  56. Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 2001; 69: 1186–1197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kaelin WG Jr . SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling. Cancer Cell 2009; 16: 180–182.

    Article  CAS  PubMed  Google Scholar 

  58. Guzy RD, Sharma B, Bell E, Chandel NS, Schumacker PT . Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol 2008; 28: 718–731.

    Article  CAS  PubMed  Google Scholar 

  59. Scatena R, Bottoni P, Botta G, Martorana GE, Giardina B . The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic. Am J Physiol Cell Physiol 2007; 293: C12–C21.

    Article  CAS  PubMed  Google Scholar 

  60. Ishii T, Yasuda K, Akatsuka A, Hino O, Hartman PS, Ishii N . A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis. Cancer Res 2005; 65: 203–209.

    CAS  PubMed  Google Scholar 

  61. Shi Y . Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 2007; 8: 829–833.

    Article  CAS  PubMed  Google Scholar 

  62. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324: 930–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 2011; 333: 1300–1303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y . Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010; 466: 1129–1133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H et al. Inhibition of alpha-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: 1326–1338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tan AY, Manley JL . The TET family of proteins: functions and roles in disease. J Mol Cell Biol 2009; 1: 82–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Varier RA, Timmers HT . Histone lysine methylation and demethylation pathways in cancer. Biochim Biophys Acta 2011; 1815: 75–89.

    CAS  PubMed  Google Scholar 

  68. Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 2010; 463: 360–363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G, Greenman C et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet 2009; 41: 521–523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010; 468: 839–843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP . CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 1999; 96: 8681–8686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C et al. Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors. J Med Chem 2012; 55: 10090–10107.

    Article  CAS  PubMed  Google Scholar 

  73. Rawson JB, Sun Z, Dicks E, Daftary D, Parfrey PS, Green RC et al. Vitamin D intake is negatively associated with promoter methylation of the Wnt antagonist gene DKK1 in a large group of colorectal cancer patients. Nutr Cancer 2012; 64: 919–928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab 2011; 96: E1472–E1476.

    Article  CAS  PubMed  Google Scholar 

  75. van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol 2009; 10: 764–771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Leonardi R, Subramanian C, Jackowski S, Rock CO . Cancer-associated isocitrate dehydrogenase mutations inactivate NADPH-dependent reductive carboxylation. J Biol Chem 2012; 287: 14615–14620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2010; 28: 2348–2355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360: 765–773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361: 1058–1066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321: 1807–1812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 2012; 119: 1901–1903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 2012; 17: 72–79.

    Article  CAS  PubMed  Google Scholar 

  83. Shibata T, Kokubu A, Miyamoto M, Sasajima Y, Yamazaki N . Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation. Am J Pathol 2011; 178: 1395–1402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pansuriya TC, van Eijk R, d’Adamo P, van Ruler MA, Kuijjer ML, Oosting J et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 2011; 43: 1256–1261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Amary MF, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet 2011; 43: 1262–1265.

    Article  CAS  PubMed  Google Scholar 

  86. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 2011; 224: 334–343.

    Article  CAS  PubMed  Google Scholar 

  87. Murugan AK, Bojdani E, Xing M . Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun 2010; 393: 555–559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hemerly JP, Bastos AU, Cerutti JM . Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur J Endocrinol 2010; 163: 747–755.

    Article  CAS  PubMed  Google Scholar 

  89. Gaal J, Burnichon N, Korpershoek E, Roncelin I, Bertherat J, Plouin PF et al. Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 2010; 95: 1274–1278.

    Article  CAS  PubMed  Google Scholar 

  90. Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Seo SI et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer 2009; 125: 353–355.

    Article  CAS  PubMed  Google Scholar 

  91. Ward PS, Cross JR, Lu C, Weigert O, Abel-Wahab O, Levine RL et al. Identification of additional IDH mutations associated with oncometabolite R(-)-2-hydroxyglutarate production. Oncogene 2012; 31: 2491–2498.

    Article  CAS  PubMed  Google Scholar 

  92. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2010; 465: 966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012; 483: 479–483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012; 483: 474–478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19: 17–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep 2011; 12: 463–469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010; 17: 510–522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR . TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 2003; 17: 637–641.

    Article  CAS  PubMed  Google Scholar 

  99. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18: 553–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 2012; 483: 484–488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Losman JA, Looper R, Koivunen P, Lee S, Schneider RK, McMahon C et al. (R)-2-Hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013; 339: 1621–1625.

    Article  CAS  PubMed  Google Scholar 

  102. Stepinski J, Bizon D, Piec G, Angielski S . The purine nucleotide cycle activity in renal cortex and medulla. Am J Kidney Dis 1989; 14: 307–309.

    Article  CAS  PubMed  Google Scholar 

  103. Brosnan ME, Brosnan JT . Renal arginine metabolism. J Nutr 2004; 134 (10 Suppl): 2791S–2795SS discussion 6S-7S.

    Article  CAS  PubMed  Google Scholar 

  104. Yogev O, Naamati A, Pines O . Fumarase: a paradigm of dual targeting and dual localized functions. FEBS J 2011; 278: 4230–4242.

    Article  CAS  PubMed  Google Scholar 

  105. Yogev O, Yogev O, Singer E, Shaulian E, Goldberg M, Fox TD et al. Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response. PLoS Biol 2010; 8: e1000328.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 2003; 73: 95–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002; 30: 406–410.

    Article  CAS  PubMed  Google Scholar 

  108. Kiuru M, Launonen V, Hietala M, Aittomaki K, Vierimaa O, Salovaara R et al. Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. Am J Pathol 2001; 159: 825–829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA 2001; 98: 3387–3392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Linehan WM, Pinto PA, Srinivasan R, Merino M, Choyke P, Choyke L et al. Identification of the genes for kidney cancer: opportunity for disease-specific targeted therapeutics. Clin Cancer Res 2007; 13 (2 Pt 2): 671s–679ss.

    Article  CAS  PubMed  Google Scholar 

  111. Ashrafian H, O’Flaherty L, Adam J, Steeples V, Chung YL, East P et al. Expression profiling in progressive stages of fumarate-hydratase deficiency: the contribution of metabolic changes to tumorigenesis. Cancer Res 2010; 70: 9153–9165.

    Article  CAS  PubMed  Google Scholar 

  112. Ratcliffe PJ . Fumarate hydratase deficiency and cancer: activation of hypoxia signaling? Cancer Cell 2007; 11: 303–305.

    Article  CAS  PubMed  Google Scholar 

  113. Pollard P, Wortham N, Barclay E, Alam A, Elia G, Manek S et al. Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome. J Pathol 2005; 205: 41–49.

    Article  PubMed  Google Scholar 

  114. Sudarshan S, Sourbier C, Kong HS, Block K, Valera Romero VA, Yang Y et al. Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol 2009; 29: 4080–4090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Koivunen P, Hirsila M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J . Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem 2007; 282: 4524–4532.

    Article  CAS  PubMed  Google Scholar 

  116. Hewitson KS, Lienard BM, McDonough MA, Clifton IJ, Butler D, Soares AS et al. Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates. J Biol Chem 2007; 282: 3293–3301.

    Article  CAS  PubMed  Google Scholar 

  117. Pollard PJ, Ratcliffe PJ . Cancer. Puzzling patterns of predisposition. Science 2009; 324: 192–194.

    Article  CAS  PubMed  Google Scholar 

  118. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399: 271–275.

    Article  CAS  PubMed  Google Scholar 

  119. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001; 107: 43–54.

    Article  CAS  PubMed  Google Scholar 

  120. Bruick RK, McKnight SL . A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001; 294: 1337–1340.

    Article  CAS  PubMed  Google Scholar 

  121. O’Flaherty L, Adam J, Heather LC, Zhdanov AV, Chung YL, Miranda MX et al. Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism. Hum Mol Genet 2010; 19: 3844–3851.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Yang M, Soga T, Pollard PJ, Adam J . The emerging role of fumarate as an oncometabolite. Front Oncol 2012; 2: 85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kaelin WG Jr . The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer 2008; 8: 865–873.

    Article  CAS  PubMed  Google Scholar 

  124. Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK, Salovaara R, Herva R, Koivisto PA et al. Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med Genet 2006; 43: 523–526.

    Article  CAS  PubMed  Google Scholar 

  125. Adam J, Ratcliffe PJ, Pollard PJ . Novel insights into FH-associated disease are KEAPing the lid on oncogenic HIF signalling. Oncotarget 2011; 2: 820–821.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Frizzell N, Lima M, Baynes JW . Succination of proteins in diabetes. Free Radic Res 2011; 45: 101–109.

    Article  CAS  PubMed  Google Scholar 

  127. Nagai R, Brock JW, Blatnik M, Baatz JE, Bethard J, Walla MD et al. Succination of protein thiols during adipocyte maturation: a biomarker of mitochondrial stress. J Biol Chem 2007; 282: 34219–34228.

    Article  CAS  PubMed  Google Scholar 

  128. Alderson NL, Wang Y, Blatnik M, Frizzell N, Walla MD, Lyons TJ et al. S-(2-Succinyl)cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate. Arch Biochem Biophys 2006; 450: 1–8.

    Article  CAS  PubMed  Google Scholar 

  129. Frizzell N, Rajesh M, Jepson MJ, Nagai R, Carson JA, Thorpe SR et al. Succination of thiol groups in adipose tissue proteins in diabetes: succination inhibits polymerization and secretion of adiponectin. J Biol Chem 2009; 284: 25772–25781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Blatnik M, Thorpe SR, Baynes JW . Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes. Ann N Y Acad Sci 2008; 1126: 272–275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Blatnik M, Frizzell N, Thorpe SR, Baynes JW . Inactivation of glyceraldehyde-3-phosphate dehydrogenase by fumarate in diabetes: formation of S-(2-succinyl)cysteine, a novel chemical modification of protein and possible biomarker of mitochondrial stress. Diabetes 2008; 57: 41–49.

    Article  CAS  PubMed  Google Scholar 

  132. Thomas SA, Storey KB, Baynes JW, Frizzell N . Tissue distribution of S-(2-succino)cysteine (2SC), a biomarker of mitochondrial stress in obesity and diabetes. Obesity (Silver Spring) 2012; 20: 263–269.

    Article  CAS  Google Scholar 

  133. Maxwell PH . Seeing the smoking gun: a sensitive and specific method to visualize loss of the tumour suppressor, fumarate hydratase, in human tissues. J Pathol 2011; 225: 1–3.

    Article  CAS  PubMed  Google Scholar 

  134. Bardella C, El-Bahrawy M, Frizzell N, Adam J, Ternette N, Hatipoglu E et al. Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J Pathol 2011; 225: 4–11.

    Article  CAS  PubMed  Google Scholar 

  135. Zhang DD . Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 2006; 38: 769–789.

    Article  CAS  PubMed  Google Scholar 

  136. Taguchi K, Motohashi H, Yamamoto M . Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 2011; 16: 123–140.

    Article  CAS  PubMed  Google Scholar 

  137. Hayes JD, McMahon M . NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 2009; 34: 176–188.

    Article  CAS  PubMed  Google Scholar 

  138. Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 2011; 20: 511–523.

    Article  CAS  PubMed  Google Scholar 

  139. Ooi A, Dykema K, Ansari A, Petillo D, Snider J, Kahnoski R et al. CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma. Cancer Res 2013; 73: 2044–2051.

    Article  CAS  PubMed  Google Scholar 

  140. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 2012; 22: 66–79.

    Article  CAS  PubMed  Google Scholar 

  141. Itoh K . [Disease regulation by Nrf2 antioxidant system]. Seikagaku 2009; 81: 447–455.

    CAS  PubMed  Google Scholar 

  142. Nguyen T, Nioi P, Pickett CB . The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 2009; 284: 13291–13295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT . Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal 2010; 13: 1713–1748.

    Article  CAS  PubMed  Google Scholar 

  144. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011; 475: 106–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L et al. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 2011; 477: 225–228.

    Article  CAS  PubMed  Google Scholar 

  146. Shambaugh GE 3rd . Urea biosynthesis I. The urea cycle and relationships to the citric acid cycle. Am J Clin Nutr 1977; 30: 2083–2087.

    Article  CAS  PubMed  Google Scholar 

  147. Adam J, Yang M, Bauerschmidt C, Kitagawa M, O’Flaherty F, Maheswaran P et al. A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia. Cell reports 2013; S2211-1247: 00173–00173.

    Google Scholar 

  148. Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 2012; 481: 385–388.

    Article  CAS  Google Scholar 

  149. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2012; 481: 380–384.

    Article  CAS  Google Scholar 

  150. Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci USA 2011; 108: 19611–19616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kaelin WG Jr . Synthetic lethality: a framework for the development of wiser cancer therapeutics. Genome Med 2009; 1: 99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Rankin EB, Tomaszewski JE, Haase VH . Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res 2006; 66: 2576–2583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Traykova-Brauch M, Schonig K, Greiner O, Miloud T, Jauch A, Bode M et al. An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice. Nat Med 2008; 14: 979–984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 2011; 469: 539–542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Copeland NG, Jenkins NA . Harnessing transposons for cancer gene discovery. Nat Rev Cancer 2010; 10: 696–706.

    Article  CAS  PubMed  Google Scholar 

  156. Dupuy AJ, Akagi K, Largaespada DA, Copeland NG, Jenkins NA . Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 2005; 436: 221–226.

    Article  CAS  PubMed  Google Scholar 

  157. Koglin N, Mueller A, Berndt M, Schmitt-Willich H, Toschi L, Stephens AW et al. Specific PET imaging of xC- transporter activity using a (1)(8)F-labeled glutamate derivative reveals a dominant pathway in tumor metabolism. Clin Cancer Res 2011; 17: 6000–6011.

    Article  CAS  PubMed  Google Scholar 

  158. Qu W, Zha Z, Ploessl K, Lieberman BP, Zhu L, Wise DR et al. Synthesis of optically pure 4-fluoro-glutamines as potential metabolic imaging agents for tumors. J Am Chem Soc 2011; 133: 1122–1133.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The Cancer Biology and Metabolism Group, led by Dr Pollard, is funded by the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no. 310837 and Cancer Research UK. Professor Soga is funded from a Grant-in-Aid for scientific research on Innovative Areas, Japan No. 22134007 and the Yamagata Prefectural Government and City of Tsuruoka.

Author information

Authors and Affiliations

  1. Nuffield Department of Medicine, Cancer biology and Metabolism Group, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK

    J Adam, M Yang & P J Pollard

  2. Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Yamagata, Japan

    T Soga

  3. Oxford-Keio Metabolomics Consortium, Keio University, Yamagata, Japan

    T Soga

  4. Oxford-Keio Metabolomics Consortium, Oxford, UK

    P J Pollard

Authors
  1. J Adam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Soga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P J Pollard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P J Pollard.

Ethics declarations

Competing interests

Professor Soga is a founder of Human Metabolome Technologies. The remaining authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Adam, J., Yang, M., Soga, T. et al. Rare insights into cancer biology. Oncogene 33, 2547–2556 (2014). https://doi.org/10.1038/onc.2013.222

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.222

Keywords

This article is cited by

Search

Advanced search

Quick links