[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
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.

  • Opinion
  • Published:

How does SIRT1 affect metabolism, senescence and cancer?

Nature Reviews Cancer volume 9, pages 123–128 (2009)Cite this article

Abstract

SIRT1 is a multifaceted, NAD+-dependent protein deacetylase that is involved in a wide variety of cellular processes from cancer to ageing. The function of SIRT1 in cancer is complex: SIRT1 has been shown to have oncogenic properties by downregulating p53 activity, but recent studies indicate that SIRT1 acts as a tumour suppressor in a mutated p53 background, raising intriguing questions regarding its mechanism of action. Here we discuss the current understanding of how SIRT1 functions in light of recent discoveries and propose that the net outcome of the seemingly opposite oncogenic and tumour-suppressive effects of SIRT1 depends on the status of p53.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: SIRT1 pathway overview.
Figure 2: Chemotherapeutic targeting of the p53–SIRT1 pathway.

Similar content being viewed by others

References

  1. Bordone, L. & Guarente, L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nature Rev. Mol. Cell Biol. 6, 298–305 (2005).

    Article  CAS  Google Scholar 

  2. Campisi, J. Suppressing cancer: the importance of being senescent. Science 309, 886–887 (2005).

    Article  CAS  Google Scholar 

  3. Wang, C. et al. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nature Cell Biol. 8, 1025–1031 (2006).

    Article  CAS  Google Scholar 

  4. Nahle, Z. et al. Direct coupling of the cell cycle and cell death machinery by E2F. Nature Cell Biol. 4, 859–864 (2002).

    Article  CAS  Google Scholar 

  5. Ford, J., Jiang, M. & Milner, J. Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res. 65, 10457–10463 (2005).

    Article  CAS  Google Scholar 

  6. Nemoto, S., Fergusson, M. M. & Finkel, T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 306, 2105–2108 (2004).

    Article  CAS  Google Scholar 

  7. Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).

    Article  CAS  Google Scholar 

  8. Tang, Y., Zhao, W., Chen, Y., Zhao, Y. & Gu, W. Acetylation is indispensable for p53 activation. Cell 133, 612–626 (2008).

    Article  CAS  Google Scholar 

  9. Feng, L., Lin, T., Uranishi, H., Gu, W. & Xu, Y. Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol. Cell. Biol. 25, 5389–5395 (2005).

    Article  CAS  Google Scholar 

  10. Krummel, K. A., Lee, C. J., Toledo, F. & Wahl, G. M. The C-terminal lysines fine-tune P53 stress responses in a mouse model but are not required for stability control or transactivation. Proc. Natl Acad. Sci. USA 102, 10188–10193 (2005).

    Article  CAS  Google Scholar 

  11. An, W., Kim, J. & Roeder, R. G. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 117, 735–748 (2004).

    Article  CAS  Google Scholar 

  12. Espinosa, J. M. & Emerson, B. M. Transcriptional regulation by p53 through intrinsic DNA/chromatin binding and site-directed cofactor recruitment. Mol. Cell 8, 57–69 (2001).

    Article  CAS  Google Scholar 

  13. Chen, W. Y. et al. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123, 437–448 (2005).

    Article  CAS  Google Scholar 

  14. Chen, W. Y. et al. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nature Genet. 33, 197–202 (2003).

    Article  CAS  Google Scholar 

  15. Chen, W. et al. Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer Cell 6, 387–398 (2004).

    Article  CAS  Google Scholar 

  16. Huffman, D. M. et al. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res. 67, 6612–6618 (2007).

    Article  CAS  Google Scholar 

  17. Abdelmohsen, K. et al. Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Mol. Cell 25, 543–557 (2007).

    Article  CAS  Google Scholar 

  18. Yamakuchi, M., Ferlito, M. & Lowenstein, C. J. miR-34a repression of SIRT1 regulates apoptosis. Proc. Natl Acad. Sci. USA 105, 13421–13426 (2008).

    Article  CAS  Google Scholar 

  19. Kim, E. J., Kho, J. H., Kang, M. R. & Um, S. J. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol. Cell 28, 277–290 (2007).

    Article  CAS  Google Scholar 

  20. Kim, J. E., Chen, J. & Lou, Z. DBC1 is a negative regulator of SIRT1. Nature 451, 583–586 (2008).

    Article  CAS  Google Scholar 

  21. Zhao, W. et al. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451, 587–590 (2008).

    Article  CAS  Google Scholar 

  22. Hasegawa, K. & Yoshikawa, K. Necdin regulates p53 acetylation via Sirtuin1 to modulate DNA damage response in cortical neurons. J. Neurosci. 28, 8772–8784 (2008).

    Article  CAS  Google Scholar 

  23. Lombard, D. B. et al. DNA repair, genome stability, and aging. Cell 120, 497–512 (2005).

    Article  CAS  Google Scholar 

  24. Pearson, M. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207–210 (2000).

    Article  CAS  Google Scholar 

  25. Cheng, H. L. et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl Acad. Sci. USA 100, 10794–10799 (2003).

    Article  CAS  Google Scholar 

  26. Chua, K. F. et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell. Metab. 2, 67–76 (2005).

    Article  CAS  Google Scholar 

  27. Langley, E. et al. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 21, 2383–2396 (2002).

    Article  CAS  Google Scholar 

  28. Wang, R. H. et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14, 312–323 (2008).

    Article  CAS  Google Scholar 

  29. Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008).

    Article  CAS  Google Scholar 

  30. Yuan, Z., Zhang, X., Sengupta, N., Lane, W. S. & Seto, E. SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol. Cell 27, 149–162 (2007).

    Article  CAS  Google Scholar 

  31. Krtolica, A. & Campisi, J. Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int. J. Biochem. Cell Biol. 34, 1401–1414 (2002).

    Article  CAS  Google Scholar 

  32. Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).

    Article  CAS  Google Scholar 

  33. Saunders, L. R. & Verdin, E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 26, 5489–5504 (2007).

    Article  CAS  Google Scholar 

  34. Motta, M. C. et al. Mammalian SIRT1 represses forkhead transcription factors. Cell 116, 551–563 (2004).

    Article  CAS  Google Scholar 

  35. Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004).

    Article  CAS  Google Scholar 

  36. Firestein, R. et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3, e2020 (2008).

    Article  Google Scholar 

  37. Wang, R. H. et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol. Cell 32, 11–20 (2008).

    Article  Google Scholar 

  38. Bradbury, C. A. et al. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia 19, 1751–1759 (2005).

    Article  CAS  Google Scholar 

  39. Hida, Y., Kubo, Y., Murao, K. & Arase, S. Strong expression of a longevity-related protein, SIRT1, in Bowen's disease. Arch. Dermatol. Res. 299, 103–106 (2007).

    Article  CAS  Google Scholar 

  40. Stunkel, W. et al. Function of the SIRT1 protein deacetylase in cancer. Biotechnol. J. 2, 1360–1368 (2007).

    Article  CAS  Google Scholar 

  41. Huang, J. et al. SIRT1 overexpression antagonizes cellular senescence with activated ERK/S6k1 signaling in human diploid fibroblasts. PLoS ONE 3, e1710 (2008).

    Article  Google Scholar 

  42. Fulda, S. & Debatin, K. M. Resveratrol modulation of signal transduction in apoptosis and cell survival: a mini-review. Cancer Detect. Prev. 30, 217–223 (2006).

    Article  CAS  Google Scholar 

  43. Vaquero, A. et al. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol. Cell 16, 93–105 (2004).

    Article  CAS  Google Scholar 

  44. Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet. 37, 391–400 (2005).

    Article  CAS  Google Scholar 

  45. van der Veer, E. et al. Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. J. Biol. Chem. 282, 10841–10845 (2007).

    Article  CAS  Google Scholar 

  46. Zhang, Q. et al. Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex. Proc. Natl Acad. Sci. USA 104, 829–833 (2007).

    Article  CAS  Google Scholar 

  47. Chen, D. et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 22, 1753–1757 (2008).

    Article  CAS  Google Scholar 

  48. Jackson, M. D., Schmidt, M. T., Oppenheimer, N. J. & Denu, J. M. Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases. J. Biol. Chem. 278, 50985–50998 (2003).

    Article  CAS  Google Scholar 

  49. Lim, C. S., Potts, M. & Helm, R. F. Nicotinamide extends the replicative life span of primary human cells. Mech. Ageing Dev. 127, 511–514 (2006).

    Article  CAS  Google Scholar 

  50. Nayagam, V. M. et al. SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. J. Biomol. Screen. 11, 959–967 (2006).

    Article  CAS  Google Scholar 

  51. Heltweg, B. et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66, 4368–4377 (2006).

    Article  CAS  Google Scholar 

  52. Solomon, J. M. et al. Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol. Cell. Biol. 26, 28–38 (2006).

    Article  CAS  Google Scholar 

  53. Lain, S. et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13, 454–463 (2008).

    Article  CAS  Google Scholar 

  54. Brooks, C. L. & Gu, W. p53 ubiquitination: Mdm2 and beyond. Mol. Cell 21, 307–315 (2006).

    Article  CAS  Google Scholar 

  55. Lim, C. S. Human SIRT1: a potential biomarker for tumorigenesis? Cell Biol. Int. 31, 636–637 (2007).

    Article  CAS  Google Scholar 

  56. Westphal, C. H., Dipp, M. A. & Guarente, L. A therapeutic role for sirtuins in diseases of aging? Trends Biochem. Sci. 32, 555–560 (2007).

    Article  CAS  Google Scholar 

  57. Jones, J. M. et al. Absence of p53 in a mouse mammary tumor model promotes tumor cell proliferation without affecting apoptosis. Cell Growth Differ. 8, 829–838 (1997).

    CAS  PubMed  Google Scholar 

  58. Mai, V. et al. Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in ApcMin mice through different mechanisms. Cancer Res. 63, 1752–1755 (2003).

    CAS  PubMed  Google Scholar 

  59. Berrigan, D., Perkins, S. N., Haines, D. C. & Hursting, S. D. Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice. Carcinogenesis 23, 817–822 (2002).

    Article  CAS  Google Scholar 

  60. Cohen, H. Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390–392 (2004).

    Article  CAS  Google Scholar 

  61. Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).

    Article  CAS  Google Scholar 

  62. Sun, C. et al. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell. Metab. 6, 307–319 (2007).

    Article  CAS  Google Scholar 

  63. Li, X. et al. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol. Cell 28, 91–106 (2007).

    Article  Google Scholar 

  64. Picard, F. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429, 771–776 (2004).

    Article  CAS  Google Scholar 

  65. Moynihan, K. A. et al. Increased dosage of mammalian Sir2 in pancreatic β cells enhances glucose-stimulated insulin secretion in mice. Cell. Metab. 2, 105–117 (2005).

    Article  CAS  Google Scholar 

  66. Banks, A. et al. SIRT1 gain of function increases energy efficient and prevents diabetes in mice. Cell Metab. 8, 333–341 (2008).

    Article  CAS  Google Scholar 

  67. Boily, G. et al. SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE 3, e1759 (2008).

    Article  Google Scholar 

  68. de Lange, T. Protection of mammalian telomeres. Oncogene 21, 532–540 (2002).

    Article  CAS  Google Scholar 

  69. Ben-Porath, I. & Weinberg, R. A. When cells get stressed: an integrative view of cellular senescence. J. Clin. Invest. 113, 8–13 (2004).

    Article  CAS  Google Scholar 

  70. Espejel, S. & Blasco, M. A. Identification of telomere-dependent “senescence-like” arrest in mouse embryonic fibroblasts. Exp. Cell Res. 276, 242–248 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from NIH/NCI to W.G. W.G. is an Ellison Medical Foundation Senior Scholar in Aging.

Author information

Authors and Affiliations

  1. Christopher L. Brooks and Wei Gu are at the Institute for Cancer Genetics and Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.,

    Christopher L. Brooks & Wei Gu

Authors
  1. Christopher L. Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Gu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary

etoposide

resveratrol

Pathway Interaction Database

p53

FURTHER INFORMATION

W. Gu's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brooks, C., Gu, W. How does SIRT1 affect metabolism, senescence and cancer?. Nat Rev Cancer 9, 123–128 (2009). https://doi.org/10.1038/nrc2562

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2562

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing