Abstract
The study of cancer metabolism has evolved vastly beyond the remit of tumour proliferation and survival with the identification of the role of ‘oncometabolites’ in tumorigenesis. Simply defined, oncometabolites are conventional metabolites that, when aberrantly accumulated, have pro-oncogenic functions. Their discovery has led researchers to revisit the Warburg hypothesis, first postulated in the 1950s, of aberrant metabolism as an aetiological determinant of cancer. As such, the identification of oncometabolites and their utilization in diagnostics and prognostics, as novel therapeutic targets and as biomarkers of disease, are areas of considerable interest in oncology. To date, fumarate, succinate, l-2-hydroxyglutarate (l-2-HG) and d-2-hydroxyglutarate (d-2-HG) have been characterized as bona fide oncometabolites. Extensive metabolic reprogramming occurs during tumour initiation and progression in renal cell carcinoma (RCC) and three oncometabolites — fumarate, succinate and l-2-HG — have been implicated in this disease process. All of these oncometabolites inhibit a superfamily of enzymes known as α-ketoglutarate-dependent dioxygenases, leading to epigenetic dysregulation and induction of pseudohypoxic phenotypes, and also have specific pro-oncogenic capabilities. Oncometabolites could potentially be exploited for the development of novel targeted therapies and as biomarkers of disease.
Key points
Oncometabolites are aberrantly accumulated metabolites that possess pro-oncogenic capabilities, they contribute to tumorigenesis via epigenetic dysregulation and can influence tumour progression through phenotypic switches such as epithelial to mesenchymal transition.
l-2-hydroxyglutarate, fumarate and succinate are bona fide renal cell carcinoma (RCC) oncometabolites; exploitation of these oncometabolites and their downstream signalling effects are attractive targets for novel therapies and as biomarkers of disease.
Oncometabolites have shared pro-oncogenic functions owing to their ability to inhibit α-ketoglutarate-dependent dioxygenases as well as individual oncometabolite-specific functions.
Chromatin remodelling via oncometabolites may recapitulate the effects of other epigenetic modifiers mutated in RCC, thus converging on the same gene signature; identification of the underlying pathways influences treatment strategy.
Elucidation of exogenous factors that give rise to oncometabolite production, such as hyperglycaemia, may prove to be a synergistic strategy to reduce the levels of oncometabolites and their subsequent sequelae.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).
Bhatt, J. R. & Finelli, A. Landmarks in the diagnosis and treatment of renal cell carcinoma. Nat. Rev. Urol. 11, 517–525 (2014).
Linehan, W. M., Walther, M. M. & Zbar, B. The genetic basis of cancer of the kidney. J. Urol. 170, 2163–2172 (2003).
Moch, H., Cubilla, A. L., Humphrey, P. A., Reuter, V. E. & Ulbright, T. M. The 2016 WHO Classification of tumours of the urinary system and male genital organs — part a: renal, penile, and testicular tumours. Eur. Urol. 70, 93–105 (2016).
Ricketts, C. J. et al. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 0, (2018).
Young, M. D. et al. Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science 361, 594–599 (2018).
Mitchell, T. J. et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx Renal. Cell 173, 611–623 (2018).
Turajlic, S. et al. Deterministic evolutionary trajectories influence primary tumor growth: TRACERx renal. Cell 173, 595–610 (2018).
Turajlic, S. et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. Cell 173, 581–594 (2018).
The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).
Zbar, B., Brauch, H., Talmadge, C. & Linehan, M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 327, 721 (1987).
Sato, Y. et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 45, 860–867 (2013).
Hosen, I. et al. TERT promoter mutations in clear cell renal cell carcinoma. Int. J. Cancer 136, 2448–2452 (2015).
Shroff, E. H. et al. MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc. Natl Acad. Sci. USA 112, 6539–6544 (2015).
Tang, S.-W. et al. MYC pathway is activated in clear cell renal cell carcinoma and essential for proliferation of clear cell renal cell carcinoma cells. Cancer Lett. 273, 35–43 (2009).
The Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30, 406–410 (2002).
Linehan, W. M. & Ricketts, C. J. The metabolic basis of kidney cancer. Semin. Cancer Biol. 23, 46–55 (2013).
Linehan, W. M., Srinivasan, R. & Schmidt, L. S. The genetic basis of kidney cancer: a metabolic disease. Nat. Rev. Urol. 7, 277–285 (2010).
Jaakkola, P. et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).
Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).
Pescador, N. et al. Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1. PLOS ONE 5, e9644 (2010).
Semenza, G. L. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Invest. 123, 3664–3671 (2013).
Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl. Acad. Sci. USA 108, 19611–19616 (2011).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).
Isaacs, J. S. 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 8, 143–153 (2005).
Pollard, P. J. 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. 14, 2231–2239 (2005).
Sudarshan, S. et al. Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2α accumulation and promotes migration and invasion. PLOS ONE 6, e21037 (2011).
Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).
Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R. & Kaelin, W. G. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4, 147–158 (2003).
Li, B. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251–255 (2014).
Du, W. et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat. Commun. 8, 1–12 (2017).
Ward, P. S. & Thompson, C. B. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21, 297–308 (2012).
Goodacre, R., Vaidyanathan, S., Dunn, W. B., Harrigan, G. G. & Kell, D. B. Metabolomics by numbers: acquiring and understanding global metabolite data. Trends Biotechnol. 22, 245–252 (2004).
Horgan, R. P. & Kenny, L. C. ‘Omic’ technologies: genomics, transcriptomics, proteomics and metabolomics. Obstet. Gynaecol. 13, 189–195 (2011).
Gouirand, V., Guillaumond, F. & Vasseur, S. Influence of the tumor microenvironment on cancer cells metabolic reprogramming. Front. Oncol 8, 117 (2018).
Yang, L. V. Tumor microenvironment and metabolism. Int. J. Mol. Sci. 18, E2729 (2017).
Hakimi, A. A. et al. An integrated metabolic atlas of clear cell renal cell carcinoma. Cancer Cell 29, 104–116 (2016).
Wettersten, H. I. et al. Grade-dependent metabolic reprogramming in kidney cancer revealed by combined proteomics and metabolomics analysis. Cancer Res. 75, 2541–2552 (2015).
van der Mijn, J. C. et al. Novel drugs that target the metabolic reprogramming in renal cell cancer. Cancer Metab. 4, 14 (2016).
Astuti, D. et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 69, 49–54 (2001).
Niemann, S. & Müller, U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat. Genet. 26, 268–270 (2000).
Warburg, O. The metabolism of carcinoma cells. J. Cancer Res. 9, 148–163 (1925).
Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).
Racker, E. Bioenergetics and the problem of tumor growth. Am. Sci. 60, 56–63 (1972).
Flier, J. S., Mueckler, M. M., Usher, P. & Lodish, H. F. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 235, 1492–1495 (1987).
Frezza, C., Pollard, P. J. & Gottlieb, E. Inborn and acquired metabolic defects in cancer. J. Mol. Med. 89, 213–220 (2011).
Haber, D. A. & Fearon, E. R. The promise of cancer genetics. Lancet 351, SII1–SII8 (1998).
Liberti, M. V. & Locasale, J. W. The warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).
Baysal, B. E. et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848–851 (2000).
Cervera, A. M., Apostolova, N., Crespo, F. L., Mata, M. & McCreath, K. J. Cells silenced for SDHB expression display characteristic features of the tumor phenotype. Cancer Res. 68, 4058–4067 (2008).
Dahia, P. L. M. et al. A HIF1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLOS Genet. 1, (2005).
López-Jiménez, E. et al. Research resource: transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol. Endocrinol. 24, 2382–2391 (2010).
Pollard, P. 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. 205, 41–49 (2005).
Vanharanta, S. et al. Distinct expression profile in fumarate-hydratase-deficient uterine fibroids. Hum. Mol. Genet. 15, 97–103 (2006).
Mohlin, S., Wigerup, C., Jögi, A. & Påhlman, S. Hypoxia, pseudohypoxia and cellular differentiation. Exp. Cell Res. 356, 192–196 (2017).
Wigerup, C., Påhlman, S. & Bexell, D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol. Ther. 164, 152–169 (2016).
Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).
Achouri, Y. et al. Identification of a dehydrogenase acting on D-2-hydroxyglutarate. Biochem. J. 381, 35–42 (2004).
Collins, R. R. J., Patel, K., Putnam, W. C., Kapur, P. & Rakheja, D. Oncometabolites: a new paradigm for oncology, metabolism, and the clinical laboratory. Clin. Chem. 63, 1812–1820 (2017).
Linster, C. L., Van Schaftingen, E. & Hanson, A. D. Metabolite damage and its repair or pre-emption. Nat. Chem. Biol. 9, 72–80 (2013).
Struys, E. A. 2-Hydroxyglutarate is not a metabolite; d-2-hydroxyglutarate and l-2-hydroxyglutarate are! Proc. Natl Acad. Sci. USA 110, E4939 (2013).
Aghili, M., Zahedi, F. & Rafiee, E. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J. Neurooncol. 91, 233–236 (2009).
Moroni, I. et al. L-2-hydroxyglutaric aciduria and brain malignant tumors: a predisposing condition? Neurology 62, 1882–1884 (2004).
Rogers, R. E. et al. Wilms tumor in a child with L-2-hydroxyglutaric aciduria. Pediatr. Dev. Pathol. 13, 408–411 (2010).
Kranendijk, M. et al. IDH2 Mutations in patients with d-2-hydroxyglutaric aciduria. Science 330, 336–336 (2010).
Morin, A., Letouzé, E., Gimenez-Roqueplo, A.-P. & Favier, J. Oncometabolites-driven tumorigenesis: from genetics to targeted therapy. Int. J. Cancer 135, 2237–2248 (2014).
Sciacovelli, M. & Frezza, C. Oncometabolites: unconventional triggers of oncogenic signalling cascades. Free Radic. Biol. Med. 100, 175–181 (2016).
Castro-Vega, L. J. et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum. Mol. Genet. 23, 2440–2446 (2014).
Kaelin, W. G. SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling. Cancer Cell 16, 180–182 (2009).
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Gross, S. et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J. Exp. Med. 207, 339–344 (2010).
Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).
Mukherjee, P. K. et al. Metabolomic analysis identifies differentially produced oral metabolites, including the oncometabolite 2-hydroxyglutarate, in patients with head and neck squamous cell carcinoma. BBA Clin. 7, 8–15 (2017).
Shelar, S. et al. Biochemical and epigenetic insights into l-2-hydroxyglutarate, a potential therapeutic target in renal cancer. Clin. Cancer Res. 24, 6433–6446 (2018).
Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016).
Bardella Chiara et al. Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J. Pathol. 225, 4–11 (2011).
Kinch, L., Grishin, N. V. & Brugarolas, J. Succination of Keap1 and activation of Nrf2-dependent antioxidant pathways in FH-deficient papillary renal cell carcinoma type-2. Cancer Cell 20, 418–420 (2011).
Gottlieb, E. & Tomlinson, I. P. M. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat. Rev. Cancer 5, 857–866 (2005).
Knudson, A. G. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).
Vranken, J. G. V., Na, U., Winge, D. R. & Rutter, J. Protein-mediated assembly of succinate dehydrogenase and its cofactors. Crit. Rev. Biochem. Mol. Biol. 50, 168–180 (2015).
Malinoc, A. et al. Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3. Endocr. Relat. Cancer 19, 283–290 (2012).
Ni, Y. et al. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am. J. Hum. Genet. 83, 261–268 (2008).
Lee, C.-H. et al. Persistent severe hyperlactatemia and metabolic derangement in lethal SDHB-mutated metastatic kidney cancer: clinical challenges and examples of extreme Warburg effect. JCO Precis. Oncol. 1, 1–14 (2017).
McEvoy, C. R. et al. SDH-deficient renal cell carcinoma associated with biallelic mutation in succinate dehydrogenase A: comprehensive genetic profiling and its relation to therapy response. NPJ Precis. Oncol. 2, 9 (2018).
Vanharanta, S. et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am. J. Hum. Genet. 74, 153–159 (2004).
Gill, A. J. et al. Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity. Am. J. Surg. Pathol. 38, 1588–1602 (2014).
Ricketts, C. J. et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J. Urol. 188, 2063–2071 (2012).
Williamson, S. R. et al. Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Mod. Pathol. 28, 80–94 (2015).
Alam, N. A. et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum. Mol. Genet. 12, 1241–1252 (2003).
Lehtonen, H. J. et al. Increased risk of cancer in patients with fumarate hydratase germline mutation. J. Med. Genet. 43, 523–526 (2006).
Linehan, W. M. & Rouault, T. A. Molecular pathways: fumarate hydratase-deficient kidney cancer — targeting the Warburg effect in cancer. Clin. Cancer Res. 19, 3345–3352 (2013).
Schmidt, L. S. & Linehan, W. M. Hereditary leiomyomatosis and renal cell carcinoma. Int. J. Nephrol. Renovasc. Dis. 7, 253–260 (2014).
Schmidt, L. S. & Linehan, W. M. Genetic predisposition to kidney cancer. Semin. Oncol. 43, 566–574 (2016).
Clark, G. R. et al. Germline FH mutations presenting with pheochromocytoma. J. Clin. Endocrinol. Metab. 99, E2046–E2050 (2014).
Neumann, H. P. H. et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292, 943–951 (2004).
Allegri, G. et al. Fumaric aciduria: an overview and the first Brazilian case report. J. Inherit. Metab. Dis. 33, 411–419 (2010).
Kerrigan, J. F., Aleck, K. A., Tarby, T. J., Bird, C. R. & Heidenreich, R. A. Fumaric aciduria: clinical and imaging features. Ann. Neurol. 47, 583–588 (2000).
Loeffen, J., Smeets, R., Voit, T., Hoffmann, G. & Smeitink, J. Fumarase deficiency presenting with periventricular cysts. J. Inherit. Metab. Dis. 28, 799–800 (2005).
Haigis, K. M., Cichowski, K. & Elledge, S. J. Tissue-specificity in cancer: the rule, not the exception. Science 363, 1150–1151 (2019).
Zheng, L. et al. Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells. Cancer Metab. 1, 12 (2013).
Wallace, D. C. Mitochondria and cancer. Nat. Rev. Cancer 12, 685–698 (2012).
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Marcucci, G. 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. 28, 2348–2355 (2010).
Lin, A.-P. et al. D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. Nat. Commun. 6, 7768 (2015).
Fan, J. et al. Human phosphoglycerate dehydrogenase produces the oncometabolite d-2-hydroxyglutarate. ACS Chem. Biol. 10, 510–516 (2015).
Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
Lee, J. H. et al. IDH1 R132C mutation is detected in clear cell hepatocellular carcinoma by pyrosequencing. World J. Surg. Oncol. 15, 82 (2017).
Shim, E.-H. et al. l-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 4, 1290–1298 (2014).
Mitchell, T. J., Rossi, S. H., Klatte, T. & Stewart, G. D. Genomics and clinical correlates of renal cell carcinoma. World J. Urol. 36, 1899–1911 (2018).
Burr, S. P. et al. Mitochondrial protein lipoylation and the 2-oxoglutarate dehydrogenase complex controls HIF1α stability in aerobic conditions. Cell Metab. 24, 740–752 (2016).
Ni, M. et al. Functional assessment of lipoyltransferase-1 deficiency in cells, mice, and humans. Cell Rep. 27, 1376–1386.e6 (2019).
Baker, P. R. et al. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain 137, 366–379 (2014).
Losman, J.-A. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621–1625 (2013).
Intlekofer, A. M. et al. Hypoxia induces production of l-2-hydroxyglutarate. Cell Metab. 22, 304–311 (2015).
Oldham, W. M., Clish, C. B., Yang, Y. & Loscalzo, J. Hypoxia-mediated increases in l-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 22, 291–303 (2015).
Nadtochiy, S. M. et al. Metabolomic profiling of the heart during acute ischemic preconditioning reveals a role for SIRT1 in rapid cardioprotective metabolic adaptation. J. Mol. Cell Cardiol. 88, 64–72 (2015).
Nadtochiy, S. M. et al. Acidic pH Is a metabolic switch for 2-hydroxyglutarate generation and signaling. J. Biol. Chem. 291, 20188–20197 (2016).
Rodenhizer, D. et al. A 3D engineered tumour for spatial snap-shot analysis of cell metabolism and phenotype in hypoxic gradients. Nat. Mater. 15, 227–234 (2016).
Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014).
Sapieha, P. et al. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat. Med. 14, 1067–1076 (2008).
Zhang, J. et al. Accumulation of succinate in cardiac ischemia primarily occurs via canonical krebs cycle activity. Cell Rep. 23, 2617–2628 (2018).
Kohlhauer Matthias et al. Metabolomic profiling in acute ST-segment–elevation myocardial infarction identifies succinate as an early marker of human ischemia–reperfusion injury. J. Am. Heart Assoc. 7, e007546
O’Flaherty, L. et al. Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism. Hum. Mol. Genet. 19, 3844–3851 (2010).
Selak, M. A., Durán, R. V. & Gottlieb, E. Redox stress is not essential for the pseudo-hypoxic phenotype of succinate dehydrogenase deficient cells. Biochim. Biophys. Acta 1757, 567–572 (2006).
Puisségur, M.-P. et al. miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ. 18, 465–478 (2011).
Blatnik, M., Frizzell, N., Thorpe, S. R. & Baynes, J. W. 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 57, 41–49 (2008).
Frizzell, N., Thomas, S. A., Carson, J. A. & Baynes, J. W. Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity. Biochem. J. 445, 247–254 (2012).
Gao, C.-L. et al. Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes. Mol. Cell. Endocrinol. 320, 25–33 (2010).
Yang, M. et al. The succinated proteome of FH-mutant tumours. Metabolites 4, 640–654 (2014).
Thomas, S. A., Storey, K. B., Baynes, J. W. & Frizzell, N. Tissue distribution of S-(2-succino)cysteine (2SC), a biomarker of mitochondrial stress in obesity and diabetes. Obesity 20, 263–269 (2012).
Guo, Y. et al. Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis. Nat. Commun. 8, 15621 (2017).
Mitchell, T. & Darley-Usmar, V. Metabolic syndrome and mitochondrial dysfunction: insights from pre-clinical studies with a mitochondrially targeted antioxidant. Free. Radic. Biol. Med. 52, 838–840 (2012).
Zhang, G.-M., Zhu, Y. & Ye, D.-W. Metabolic syndrome and renal cell carcinoma. World J. Surg. Oncol. 12, 236 (2014).
Häggström, C. et al. Metabolic factors associated with risk of renal cell carcinoma. PLOS ONE 8, e57475 (2013).
Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470.e13 (2016).
Tannahill, G. et al. Succinate is a danger signal that induces IL-1β via HIF-1α. Nature 496, 238–242 (2013).
Kaelin, W. G. Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases. Cold Spring Harb. Symp. Quant. Biol. 76, 335–345 (2011).
Xiao, M. 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. 26, 1326–1338 (2012).
Letouzé, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
Laukka, T. et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256–4265 (2016).
Guzy, R. D., Sharma, B., Bell, E., Chandel, N. S. & Schumacker, P. T. 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. 28, 718–731 (2008).
Adam, J. 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 20, 524–537 (2011).
Chowdhury, R. et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463–469 (2011).
Koivunen, P. et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484–488 (2012).
Tarhonskaya, H. et al. Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases. Nat. Commun. 5, 3423 (2014).
Cedar, H. & Bergman, Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat. Rev. Genet. 10, 295–304 (2009).
Feinberg, A. P., Ohlsson, R. & Henikoff, S. The epigenetic progenitor origin of human cancer. Nat. Rev. Genet. 7, 21–33 (2006).
Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007).
Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).
Lu, C. et al. Induction of sarcomas by mutant IDH2. Genes Dev. 27, 1986–1998 (2013).
Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).
Aspuria, P.-J. P. et al. Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism. Cancer Metab. 2, 21 (2014).
Enane, F. O., Saunthararajah, Y. & Korc, M. Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells. Cell Death Dis. 9, 1–15 (2018).
Zhou, D., Luo, Y., Dingli, D. & Traulsen, A. The invasion of de-differentiating cancer cells into hierarchical tissues. PLOS Computational Biol. 15, e1007167 (2019).
Ahuja, N. et al. Association between CpG island methylation and microsatellite instability in colorectal cancer. Cancer Res. 57, 3370–3374 (1997).
Issa, J.-P. CpG island methylator phenotype in cancer. Nat. Rev. Cancer 4, 988–993 (2004).
Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).
Linehan, W. M. et al. Comprehensive molecular characterization of papillary renal cell carcinoma. N. Engl. J. Med. 374, 135–145 (2016).
Chan, M. M. Y. et al. Cascade fumarate hydratase mutation screening allows early detection of kidney tumour: a case report. BMC Med. Genet. 18, 79 (2017).
Ooi, A. et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20, 511–523 (2011).
Sourbier, C. et al. Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell 26, 840–850 (2014).
Shanmugasundaram, K. et al. The oncometabolite fumarate promotes pseudohypoxia through noncanonical activation of NF-κB signaling. J. Biol. Chem. 289, 24691–24699 (2014).
van Uden, P., Kenneth, N. S. & Rocha, S. Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem. J. 412, 477–484 (2008).
Tong, W.-H. et al. The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels. Cancer Cell 20, 315–327 (2011).
Bratslavsky, G., Sudarshan, S., Neckers, L. & Linehan, W. M. Pseudohypoxic pathways in renal cell carcinoma. Clin. Cancer Res. 13, 4667–4671 (2007).
Sullivan, L. B. et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51, 236–248 (2013).
Zheng, L. et al. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat. Commun. 6, 6001 (2015).
Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).
van Deursen, J. M. The role of senescent cells in ageing. Nature 509, 439–446 (2014).
Fourquet, S., Guerois, R., Biard, D. & Toledano, M. B. Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation. J. Biol. Chem. 285, 8463–8471 (2010).
Jin, L. et al. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27, 257–270 (2015).
Hensley, C. T., Wasti, A. T. & DeBerardinis, R. J. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J. Clin. Invest. 123, 3678–3684 (2013).
Mullen, A. R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385–388 (2012).
Xu, Y. et al. Pathologic oxidation of ptpn12 underlies abl1 phosphorylation in hereditary leiomyomatosis and renal cell carcinoma. Cancer Res. 78, 6539–6548 (2018).
Shambaugh, G. E. Urea biosynthesis I. The urea cycle and relationships to the citric acid cycle. Am. J. Clin. Nutr. 30, 2083–2087 (1977).
Frezza, C. et al. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477, 225–228 (2011).
Mu, X. et al. Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation. Oncotarget 8, 13174–13185 (2017).
Baumbach, L., Leyssac, P. P. & Skinner, S. L. Studies on renin release from isolated superfused glomeruli: effects of temperature, urea, ouabain and ethacrynic acid. J. Physiol. 258, 243–256 (1976).
He, W. et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188–193 (2004).
Toma, I. et al. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J. Clin. Invest. 118, 2526–2534 (2008).
Aguiar, C. J. et al. Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation. Cell Commun. Signal. 12, 78 (2014).
Correa, P. R. A. V. et al. Succinate is a paracrine signal for liver damage. J. Hepatol. 47, 262–269 (2007).
Jiang, S. & Yan, W. Succinate in the cancer-immune cycle. Cancer Lett. 390, 45–47 (2017).
Mills, E. & O’Neill, L. A. J. Succinate: a metabolic signal in inflammation. Trends Cell Biol. 24, 313–320 (2014).
Zhang, Z. et al. Identification of lysine succinylation as a new post-translational modification. Nat. Chem. Biol. 7, 58–63 (2011).
Li, F. et al. NADP+-IDH mutations promote hypersuccinylation that impairs mitochondria respiration and induces apoptosis resistance. Mol. Cell 60, 661–675 (2015).
Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell Proteom. 11, 100–107 (2012).
Park, J. et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol. Cell 50, 919–930 (2013).
Frezza, C. Mitochondrial metabolites: undercover signalling molecules. Interface Focus 7, 20160100 (2017).
Cardaci, S. et al. Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat. Cell Biol. 17, 1317–1326 (2015).
Lussey-Lepoutre, C. et al. Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism. Nat. Commun. 6, 8784 (2015).
Su, R. et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA Signaling. Cell 172, 90–105.e23 (2018).
Jia, G. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885–887 (2011).
Li, Z. et al. FTO plays an oncogenic role in acute myeloid leukemia as a n6-methyladenosine rna demethylase. Cancer Cell 31, 127–141 (2017).
Fu, X. et al. 2-Hydroxyglutarate inhibits ATP synthase and mTOR signaling. Cell Metab. 22, 508–515 (2015).
Cancer Genome Atlas Research Network. et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015).
Colvin, H. et al. Oncometabolite D-2-hydroxyglurate directly induces epithelial-mesenchymal transition and is associated with distant metastasis in colorectal cancer. Sci. Rep. 6, 36289 (2016).
Adam, J. et al. A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia. Cell Rep. 3, 1440–1448 (2013).
Nassereddine, S., Lap, C. J., Haroun, F. & Tabbara, I. The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia. Ann. Hematol. 96, 1983–1991 (2017).
Kats, L. M. et al. A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML. Leukemia 31, 1466–1470 (2017).
Kernytsky, A. et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood 125, 296–303 (2015).
Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).
Birendra, K. C. & DiNardo, C. D. Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clin. Lymphoma. Myeloma. Leuk. 16, 460–465 (2016).
Norsworthy, K. J. et al. FDA approval summary: ivosidenib for relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-1 mutation. Clin. Cancer Res. 25, 3205–3209 (2019).
Terunuma, A. et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J. Clin. Invest. 124, 398–412 (2014).
Salamanca-Cardona, L. et al. In vivo imaging of glutamine metabolism to the oncometabolite 2-hydroxyglutarate in idh1/2 mutant tumors. Cell Metab. 26, 830–841.e3 (2017).
Abu Aboud, O. et al. Glutamine addiction in kidney cancer suppresses oxidative stress and can be exploited for real-time imaging. Cancer Res. 77, 6746–6758 (2017).
Gameiro, P. A. et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab 17, 372–385 (2013).
Raczka, A. M. & Reynolds, P. A. Glutaminase inhibition in renal cell carcinoma therapy. Cancer Drug Resist. 2, 356–364 (2019).
Song, M., Kim, S.-H., Im, C. Y. & Hwang, H.-J. Recent development of small molecule glutaminase inhibitors. Curr. Top Med. Chem. 18, 432–443 (2018).
Tannir, N. M. et al. CANTATA: a randomized phase 2 study of CB-839 in combination with cabozantinib vs. placebo with cabozantinib in patients with advanced/metastatic renal cell carcinoma. J. Clin. Oncol. 36, TPS4601–TPS4601 (2018).
Vancura, A., Bu, P., Bhagwat, M., Zeng, J. & Vancurova, I. Metformin as an anticancer agent. Trends Pharmacol. Sci. 39, 867–878 (2018).
Brière, J.-J. et al. Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions. Hum. Mol. Genet. 14, 3263–3269 (2005).
MacKenzie, E. D. et al. Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol. Cell. Biol. 27, 3282–3289 (2007).
Matsumoto, K. et al. 2-Oxoglutarate downregulates expression of vascular endothelial growth factor and erythropoietin through decreasing hypoxia-inducible factor-1alpha and inhibits angiogenesis. J. Cell. Physiol. 209, 333–340 (2006).
Matsumoto, K. et al. Antitumor effects of 2-oxoglutarate through inhibition of angiogenesis in a murine tumor model. Cancer Science 100, 1639–1647 (2009).
Tennant, D. A. et al. Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. Oncogene 28, 4009–4021 (2009).
Chen, W. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539, 112–117 (2016).
Cho, H. et al. On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models. Nature 539, 107–111 (2016).
Courtney, K. D. et al. Phase I dose-escalation trial of pt2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J. Clin. Oncol. 36, 867–874 (2018).
Fenaux, P. et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 10, 223–232 (2009).
Gurion, R. et al. 5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome — a systematic review and meta-analysis. Haematologica 95, 303–310 (2010).
Turcan, S. et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine. Oncotarget 4, 1729–1736 (2013).
Yoo, K. H. & Hennighausen, L. EZH2 methyltransferase and H3K27 methylation in breast cancer. Int. J. Biol. Sci. 8, 59–65 (2012).
Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).
van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521–523 (2009).
Hu, C. Y. et al. Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival. Clin. Cancer Res. 20, 4349–4360 (2014).
To, K. K. W., Zhan, Z. & Bates, S. E. Aberrant promoter methylation of the ABCG2 gene in renal carcinoma. Mol. Cell Biol. 26, 8572–8585 (2006).
Reu, F. J. et al. Overcoming resistance to interferon-induced apoptosis of renal carcinoma and melanoma cells by DNA demethylation. J. Clin. Oncol. 24, 3771–3779 (2006).
Amato, R. J. et al. MG98, a second-generation DNMT1 inhibitor, in the treatment of advanced renal cell carcinoma. Cancer Invest. 30, 415–421 (2012).
Brindle, K. M. Imaging metabolism with hyperpolarized (13)C-labeled cell substrates. J. Am. Chem. Soc. 137, 6418–6427 (2015).
Skinner, J. G. et al. Metabolic and molecular imaging with hyperpolarised tracers. Mol. Imaging Biol. 20, 902–918 (2018).
Dong, Y. et al. Hyperpolarized MRI visualizes Warburg effects and predicts treatment response to mTOR inhibitors in patient-derived ccRCC xenograft models. Cancer Res. 79, 242–250 (2018).
Casey, R. T. et al. Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility. JCO Precis. Oncol. 2, 1–12 (2018).
Lussey-Lepoutre, C. et al. In vivo detection of succinate by magnetic resonance spectroscopy as a hallmark of sdhx mutations in paraganglioma. Clin. Cancer Res. 22, 1120–1129 (2016).
Bisdas, S. et al. MR spectroscopy for in vivo assessment of the oncometabolite 2-hydroxyglutarate and its effects on cellular metabolism in human brain gliomas at 9.4T. J. Magn. Reson. Imaging 44, 823–833 (2016).
de la Fuente, M. I. et al. Integration of 2-hydroxyglutarate-proton magnetic resonance spectroscopy into clinical practice for disease monitoring in isocitrate dehydrogenase-mutant glioma. Neuro Oncol. 18, 283–290 (2016).
Kim, I.-Y., Suh, S.-H., Lee, I.-K. & Wolfe, R. R. Applications of stable, nonradioactive isotope tracers in in vivo human metabolic research. Exp. Mol. Med. 48, e203 (2016).
Süllentrop, F., Hahn, J. & Moka, D. In vitro and in vivo 1h-mr spectroscopic examination of the renal cell carcinoma. Int. J. Biomed. Sci. 8, 94–108 (2012).
Santagata, S. et al. Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery. Proc. Natl Acad. Sci. USA 111, 11121–11126 (2014).
Ljungberg, B. et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur. Urol. 67, 913–924 (2015).
Petros, F. G. et al. Oncologic outcomes of patients with positive surgical margin after partial nephrectomy: a 25-year single institution experience. World J. Urol. 36, 1093–1101 (2018).
Maxwell, P. H. Seeing the smoking gun: a sensitive and specific method to visualize loss of the tumour suppressor, fumarate hydratase, in human tissues. J. Pathol. 225, 1–3 (2011).
Yang, M., Soga, T., Pollard, P. J. & Adam, J. The emerging role of fumarate as an oncometabolite. Front. Oncol. 2, 85 (2012).
Gupta, S. et al. Primary renal paragangliomas and renal neoplasia associated with pheochromocytoma/paraganglioma: analysis of von Hippel-Lindau (VHL), succinate dehydrogenase (SDHX) and transmembrane protein 127 (TMEM127). Endocr. Pathol. 28, 253–268 (2017).
Ozluk, Y. et al. Renal carcinoma associated with a novel succinate dehydrogenase A mutation: a case report and review of literature of a rare subtype of renal carcinoma. Hum. Pathol. 46, 1951–1955 (2015).
Ricketts, C. J. et al. Tumor risks and genotype–phenotype–proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum. Mutat. 31, 41–51 (2010).
Sanchez, D. J. & Simon, M. C. Genetic and metabolic hallmarks of clear cell renal cell carcinoma. Biochim. Biophys. Acta 1870, 23–31 (2018).
Gudbjartsson, T. et al. Histological subtyping and nuclear grading of renal cell carcinoma and their implications for survival: a retrospective nation-wide study of 629 patients. Eur. Urol. 48, 593–600 (2005).
Acknowledgements
C.Y. is funded by the Wellcome Trust and The Urology Foundation. C.F. is supported by the Medical Research Council, grant MRC_MC_UU_12022/6.
Author information
Authors and Affiliations
Contributions
C.Y. C.F. and G.D.S. researched the data for the article and made substantial contributions to discussions of the content. C.Y. wrote the manuscript. C.Y. G.D.S. and C.F. reviewed and edited the manuscript before submission.
Corresponding authors
Ethics declarations
Competing interests
C.Y. declares no competing interests. G.D.S. has received educational grants from Pfizer, AstraZeneca and Intuitive Surgical, consultancy fees from Merck, Pfizer, EUSA Pharma and CMR Surgical, travel expenses from Pfizer and speaker fees from Pfizer. C.F. is an adviser of Istesso Limited and a member of the Scientific Advisory Board of Owlstone Medical.
Additional information
Peer review information
Nature Reviews Nephrology thanks J. Bedke, R. Deberardinis, J. Hsieh and R. Weiss for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Hereditary leiomyomatosis and renal cell cancer
-
(HLRCC). An autosomal dominant hereditary cancer syndrome caused by germline mutations in FH. HLRCC is characterized by cutaneous and uterine leiomyomas and is associated with papillary type 2 RCC.
- Hereditary paraganglioma
-
(PGL). A dominantly inherited rare condition consisting of benign tumours arising from neuroendocrine tissues, typically in the head and neck.
- Phaeochromocytomas
-
(PCCs). A type of paraganglioma that arises from the adrenal glands and produces catecholamines such as adrenaline.
- Pseudohypoxic phenotype
-
Hypoxic-like metabolic changes that are observed in cells in the absence of a hypoxic environment or stimulant.
- Neomorphic
-
A novel and/or non-canonical function of an enzyme.
- Heterozygous germline mutations
-
Inheritance of one copy of a mutant allele and one copy of the wild type allele.
- Loss of heterozygosity
-
(LOH). The loss of one allele of a genetic locus.
- CpG islands
-
Clusters of dinucleotide sequence of a cytosine followed by a guanosine nucleotide in the 5′–3′ direction. CpG islands are often found in promoter regions upstream of transcription sites.
- Half maximal inhibitory concentration
-
(IC50). A measure of the potency of a substance to inhibit a specific biological process or function by 50%.
- Anaplerosis
-
The process of replenishing the tricarboxylic acid cycle intermediates that have been extracted for biosynthesis.
Rights and permissions
About this article
Cite this article
Yong, C., Stewart, G.D. & Frezza, C. Oncometabolites in renal cancer. Nat Rev Nephrol 16, 156–172 (2020). https://doi.org/10.1038/s41581-019-0210-z
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41581-019-0210-z
This article is cited by
-
Prediction of metabolites associated with somatic mutations in cancers by using genome-scale metabolic models and mutation data
Genome Biology (2024)
-
Investigating the causal associations between metabolic biomarkers and the risk of kidney cancer
Communications Biology (2024)
-
Therapeutic importance and diagnostic function of circRNAs in urological cancers: from metastasis to drug resistance
Cancer and Metastasis Reviews (2024)
-
Multi-omic profiling of clear cell renal cell carcinoma identifies metabolic reprogramming associated with disease progression
Nature Genetics (2024)
-
HES1-mediated down-regulation of miR-138 sustains NOTCH1 activation and promotes proliferation and invasion in renal cell carcinoma
Journal of Experimental & Clinical Cancer Research (2023)
