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.

The uric acid transporter SLC2A9 is a direct target gene of the tumor suppressor p53 contributing to antioxidant defense

Abstract

Only humans and higher primates have high uric acid blood levels. Although high uric acid causes gout, it has been linked with human longevity because of its hypothetical antioxidant function. Recent studies reveal that p53 has significant roles in cellular metabolism. One example of this is an antioxidant function that potentially contributes to tumor suppression. Here, we reported a first beneficial link between p53 and uric acid. We identified the uric acid transporter SLC2A9 (also known as GLUT9) as a direct p53 target gene and a key downstream effector in the reduction of reactive oxygen species (ROS) through transporting uric acid as a source of antioxidant. Oxidative stress induced SLC2A9 expression in a p53-dependent manner, and inhibition of SLC2A9 by small interfering RNA (siRNA) or anti-gout drugs such as probenecid significantly increased ROS levels in an uric acid-dependent manner and greatly sensitized cancer cells to chemotherapeutic drugs. Conversely, expression of SLC2A9 reduced ROS and protected against DNA damage and cell death, suggesting its antioxidant function. The increased production of ROS because of p53 loss was rescued by SLC2A9 expression. Furthermore, decreased SLC2A9 expression was observed in several cancer types and was associated with a poorer prognosis. Our findings suggest that the p53-SLC2A9 pathway is a novel antioxidant mechanism that uses uric acid to maintain ROS homeostasis and prevent accumulation of ROS-associated damage that potentially contributes to cancer development.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Vousden KH, Prives C . Blinded by the light: the growing complexity of p53. Cell 2009; 137: 413–431.

    Article  CAS  PubMed  Google Scholar 

  2. Itahana Y, Itahana K . Emerging roles of mitochondrial p53 and ARF. Curr Drug Targets 2012; 13: 1633–1640.

    Article  CAS  PubMed  Google Scholar 

  3. Maddocks OD, Vousden KH . Metabolic regulation by p53. J Mol Med (Berl) 2011; 89: 237–245.

    Article  CAS  Google Scholar 

  4. Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 2012; 149: 1269–1283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jackson AL, Loeb LA . The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat Res 2001; 477: 7–21.

    Article  CAS  PubMed  Google Scholar 

  6. Gottlieb E, Vousden KH . p53 regulation of metabolic pathways. Cold Spring Harb Perspect Biol 2010; 2: a001040.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B . A model for p53-induced apoptosis. Nature 1997; 389: 300–305.

    Article  CAS  PubMed  Google Scholar 

  8. Macip S, Igarashi M, Berggren P, Yu J, Lee SW, Aaronson SA . Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol Cell Biol 2003; 23: 8576–8585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006; 126: 107–120.

    CAS  PubMed  Google Scholar 

  10. Budanov AV, Sablina AA, Feinstein E, Koonin EV, Chumakov PM . Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 2004; 304: 596–600.

    Article  CAS  PubMed  Google Scholar 

  11. Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z . Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA 2010; 107: 7455–7460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yoon KA, Nakamura Y, Arakawa H . Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J Hum Genet 2004; 49: 134–140.

    Article  CAS  PubMed  Google Scholar 

  13. Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM . The antioxidant function of the p53 tumor suppressor. Nat Med 2005; 11: 1306–1313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Augustin R, Carayannopoulos MO, Dowd LO, Phay JE, Moley JF, Moley KH . Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking. J Biol Chem 2004; 279: 16229–16236.

    Article  CAS  PubMed  Google Scholar 

  15. Christophorou MA, Martin-Zanca D, Soucek L, Lawlor ER, Brown-Swigart L, Verschuren EW et al. Temporal dissection of p53 function in vitro and in vivo. Nat Genet 2005; 37: 718–726.

    Article  CAS  PubMed  Google Scholar 

  16. Itahana K, Mao H, Jin A, Itahana Y, Clegg HV, Lindstrom MS et al. Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 2007; 12: 355–366.

    Article  CAS  PubMed  Google Scholar 

  17. Ringshausen I, O'Shea CC, Finch AJ, Swigart LB, Evan GI . Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 2006; 10: 501–514.

    Article  CAS  PubMed  Google Scholar 

  18. Hoh J, Jin S, Parrado T, Edington J, Levine AJ, Ott J . The p53MH algorithm and its application in detecting p53-responsive genes. Proc Natl Acad Sci USA 2002; 99: 8467–8472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vousden KH, Ryan KM . p53 and metabolism. Nat Rev Cancer 2009; 9: 691–700.

    Article  CAS  PubMed  Google Scholar 

  20. Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 1998; 282: 1497–1501.

    Article  CAS  PubMed  Google Scholar 

  21. Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 1998; 282: 1497–1501.

    Article  CAS  PubMed  Google Scholar 

  22. Phay JE, Hussain HB, Moley JF . Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9). Genomics 2000; 66: 217–220.

    Article  CAS  PubMed  Google Scholar 

  23. Anzai N, Ichida K, Jutabha P, Kimura T, Babu E, Jin CJ et al. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem 2008; 283: 26834–26838.

    Article  CAS  PubMed  Google Scholar 

  24. Caulfield MJ, Munroe PB, O'Neill D, Witkowska K, Charchar FJ, Doblado M et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med 2008; 5: e197.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008; 40: 437–442.

    Article  CAS  PubMed  Google Scholar 

  26. Matsuo H, Chiba T, Nagamori S, Nakayama A, Domoto H, Phetdee K et al. Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet 2008; 83: 744–751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bibert S, Hess SK, Firsov D, Thorens B, Geering K, Horisberger JD et al. Mouse GLUT9: evidences for a urate uniporter. Am J Physiol Renal Physiol 2009; 297: F612–F619.

    Article  CAS  PubMed  Google Scholar 

  28. Dehghan A, Kottgen A, Yang Q, Hwang SJ, Kao WL, Rivadeneira F et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 2008; 372: 1953–1961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Doring A, Gieger C, Mehta D, Gohlke H, Prokisch H, Coassin S et al. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet 2008; 40: 430–436.

    Article  PubMed  Google Scholar 

  30. Li S, Sanna S, Maschio A, Busonero F, Usala G, Mulas A et al. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet 2007; 3: e194.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ames BN, Cathcart R, Schwiers E, Hochstein P . Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA 1981; 78: 6858–6862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kellogg EW 3rd, Fridovich I . Liposome oxidation and erythrocyte lysis by enzymically generated superoxide and hydrogen peroxide. J Biol Chem 1977; 252: 6721–6728.

    CAS  PubMed  Google Scholar 

  33. Liu JW, Chandra D, Rudd MD, Butler AP, Pallotta V, Brown D et al. Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS. Oncogene 2005; 24: 2020–2031.

    Article  CAS  PubMed  Google Scholar 

  34. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z . Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 2007; 26: 1749–1760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Augustin R . The protein family of glucose transport facilitators: It's not only about glucose after all. IUBMB Life 2010; 62: 315–333.

    CAS  PubMed  Google Scholar 

  36. Oda M, Satta Y, Takenaka O, Takahata N . Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol 2002; 19: 640–653.

    Article  CAS  PubMed  Google Scholar 

  37. Wu XW, Muzny DM, Lee CC, Caskey CT . Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 1992; 34: 78–84.

    Article  CAS  PubMed  Google Scholar 

  38. So A, Thorens B . Uric acid transport and disease. J Clin Invest 2010; 120: 1791–1799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cutler RG . Antioxidants and aging. Am J Clin Nutr 1991; 53: 373S–379S.

    Article  CAS  PubMed  Google Scholar 

  40. Hooper DC, Bagasra O, Marini JC, Zborek A, Ohnishi ST, Kean R et al. Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis. Proc Natl Acad Sci USA 1997; 94: 2528–2533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kim TS, Pae CU, Yoon SJ, Jang WY, Lee NJ, Kim JJ et al. Decreased plasma antioxidants in patients with Alzheimer's disease. Int J Geriatr Psychiatry 2006; 21: 344–348.

    Article  PubMed  Google Scholar 

  42. deLau LM, Koudstaal PJ, Hofman A, Breteler MM . Serum uric acid levels and the risk of Parkinson disease. Ann Neurol 2005; 58: 797–800.

    Article  CAS  Google Scholar 

  43. Pietraforte D, Castelli M, Metere A, Scorza G, Samoggia P, Menditto A et al. Salivary uric acid at the acidic pH of the stomach is the principal defense against nitrite-derived reactive species: sparing effects of chlorogenic acid and serum albumin. Free Radic Biol Med 2006; 41: 1753–1763.

    Article  CAS  PubMed  Google Scholar 

  44. Campos-Arroyo D, Martinez-Lazcano JC, Melendez-Zajgla J . Probenecid is a chemosensitizer in cancer cell lines. Cancer Chemother Pharmacol 2012; 69: 495–504.

    Article  CAS  PubMed  Google Scholar 

  45. Preitner F, Bonny O, Laverriere A, Rotman S, Firsov D, Da Costa A et al. Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy. Proc Natl Acad Sci USA 2009; 106: 15501–15506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 2007; 448: 375–379.

    Article  CAS  PubMed  Google Scholar 

  47. Beckman KB, Ames BN . Oxidative decay of DNA. J Biol Chem 1997; 272: 19633–19636.

    Article  CAS  PubMed  Google Scholar 

  48. Itahana K, Bhat KP, Jin A, Itahana Y, Hawke D, Kobayashi R et al. Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol Cell 2003; 12: 1151–1164.

    Article  CAS  PubMed  Google Scholar 

  49. Itahana K, Zhang Y . Mitochondrial p32 is a critical mediator of ARF-induced apoptosis. Cancer Cell 2008; 13: 542–553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Clegg HV, Itahana Y, Itahana K, Ramalingam S, Zhang Y . Mdm2 RING mutation enhances p53 transcriptional activity and p53-p300 interaction. PLoS ONE 2012; 7: e38212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lei Z, Tan IB, Das K, Deng N, Zouridis H, Pattison S et al. Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology 2013; 145: 554–565.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge funding from the Singapore Ministry of Education AcRF Tier 2 fund (MOE2013-T2-1-123) and the Duke-NUS core grant. We thank Dr Gerald Evan for providing Mdm2+/+; p53ER/− and Mdm2−/−; p53ER/− MEFs, Dr. Bert Vogelstein for HCT116 (p53+/+) and HCT116 (p53−/−) cell lines, Dr Yanping Zhang for p53 and green-fluorescent protein adenoviruses. We also thank Drs David Virshup, Patrick Casey, Kanaga Sabapathy and Paul Yen for critical reading of the manuscript. We thank Lee Guan Hwee Bernard for technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to K Itahana.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Itahana, Y., Han, R., Barbier, S. et al. The uric acid transporter SLC2A9 is a direct target gene of the tumor suppressor p53 contributing to antioxidant defense. Oncogene 34, 1799–1810 (2015). https://doi.org/10.1038/onc.2014.119

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.119

This article is cited by

Search

Quick links