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.

  • Original Article
  • Published:

Dual role of SIRT1 in UVB-induced skin tumorigenesis

Oncogene volume 34, pages 357–363 (2015)Cite this article

Subjects

Abstract

The protein deacetylase SIRT1 regulates various pathways in metabolism, aging and cancer. However, the role of SIRT1 in skin cancer remains unclear. Here, using mice with targeted deletions of SIRT1 in their epidermis in both resistant B6 and sensitive SKH1 hairless backgrounds, we show that the role of SIRT1 in skin cancer development induced by ultraviolet B (UVB) radiation is dependent on its gene dose. Keratinocyte-specific heterozygous deletion of SIRT1 promotes UVB-induced skin tumorigenesis, whereas homozygous deletion of SIRT1 suppresses skin tumor development but sensitizes the B6 mice to chronic solar injury. In mouse skin, SIRT1 is haploinsufficient for UVB-induced DNA damage repair and expression of xeroderma pigmentosum C (XPC), a protein critical for repairing UVB-induced DNA damage. As compared with normal human skin, downregulation of SIRT1 is in parallel with downregulation of XPC in human cutaneous squamous cell carcinoma at both the protein and mRNA levels. In contrast, homozygous SIRT1 deletion in mouse skin augments p53 acetylation and expression of its transcriptional target Noxa, and sensitizes the epidermis to UVB-induced apoptosis in vivo, while heterozygous SIRT1 deletion has no such effect. The gene dosage-dependent function of SIRT1 in DNA repair and cell survival is consistent with the dual roles of SIRT1 in UVB-induced skin tumorigenesis. Our results reveal the gene dosage-dependent in vivo functions of SIRT1 in skin tumorigenesis and may shed light on the role of SIRT1 in epithelial cancer induced by DNA damage.

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
Figure 4
Figure 5

Similar content being viewed by others

Abbreviations

cHet:

keratinocyte-specific heterozygous SIRT1 deletion

cKO:

keratinocyte-specific homozygous SIRT1 deletion

NHEK:

normal human epidermal keratinocytes

PAP:

papilloma

SCC:

squamous cell carcinoma

SIRT1:

sirtuin 1

UVB:

ultraviolet B

WT:

wild-type

XP:

xeroderma pigmentosum

XPC:

xeroderma pigmentosum group C.

References

  1. Haigis MC, Guarente LP . Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev 2006; 20: 2913–2921.

    Article  CAS  Google Scholar 

  2. Blander G, Guarente L . The Sir2 family of protein deacetylases. Annu Rev Biochem 2004; 73: 417–435.

    Article  CAS  Google Scholar 

  3. Michan S, Sinclair D . Sirtuins in mammals: insights into their biological function. Biochem J 2007; 404: 1–13.

    Article  CAS  Google Scholar 

  4. Haigis MC, Sinclair DA . Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 2010; 5: 253–295.

    Article  CAS  Google Scholar 

  5. Brooks CL, Gu W . How does SIRT1 affect metabolism, senescence and cancer? Nat Rev Cancer 2009; 9: 123–128.

    Article  CAS  Google Scholar 

  6. Deng CX . SIRT1, is it a tumor promoter or tumor suppressor? Int J Biol Sci 2009; 5: 147–152.

    Article  CAS  Google Scholar 

  7. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 2001; 107: 137–148.

    Article  CAS  Google Scholar 

  8. Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 2001; 107: 149–159.

    Article  CAS  Google Scholar 

  9. Prives C, Manley JL . Why is p53 acetylated? Cell 2001; 107: 815–818.

    Article  CAS  Google Scholar 

  10. Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A et al. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res 2007; 67: 6612–6618.

    Article  CAS  Google Scholar 

  11. Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT et al. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia 2005; 19: 1751–1759.

    Article  CAS  Google Scholar 

  12. Stunkel W, Peh BK, Tan YC, Nayagam VM, Wang X, Salto-Tellez M et al. Function of the SIRT1 protein deacetylase in cancer. Biotechnol J 2007; 2: 1360–1368.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell 2008; 32: 11–20.

    Article  Google Scholar 

  15. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003; 425: 191–196.

    Article  CAS  Google Scholar 

  16. Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C et al. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 2004; 13: 627–638.

    Article  CAS  Google Scholar 

  17. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004; 305: 390–392.

    Article  CAS  Google Scholar 

  18. Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 2008; 14: 312–323.

    Article  CAS  Google Scholar 

  19. Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One 2008; 3: e2020.

    Article  Google Scholar 

  20. Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 2008; 135: 907–918.

    Article  CAS  Google Scholar 

  21. Herranz D, Munoz-Martin M, Canamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 2010; 1: 3.

    Article  Google Scholar 

  22. Powell MJ, Casimiro MC, Cordon-Cardo C, He X, Yeow WS, Wang C et al. Disruption of a Sirt1-dependent autophagy checkpoint in the prostate results in prostatic intraepithelial neoplasia lesion formation. Cancer Res 2011; 71: 964–975.

    Article  CAS  Google Scholar 

  23. Herranz D, Serrano M . SIRT1: recent lessons from mouse models. Nat Rev Cancer. 2010; 10: 819–823.

    Article  CAS  Google Scholar 

  24. Herranz D, Maraver A, Canamero M, Gomez-Lopez G, Inglada-Perez L, Robledo M et al. SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency. Oncogene 2013; 32: 4052–4056.

    Article  CAS  Google Scholar 

  25. Yuan Z, Seto E . A functional link between SIRT1 deacetylase and NBS1 in DNA damage response. Cell Cycle 2007; 6: 2869–2871.

    Article  CAS  Google Scholar 

  26. Fan W, Luo J . SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Molecular cell 2010; 39: 247–258.

    Article  CAS  Google Scholar 

  27. Ming M, Shea CR, Guo X, Li X, Soltani K, Han W et al. Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C. Proc Natl Acad Sci USA 2010; 107: 22623–22628.

    Article  CAS  Google Scholar 

  28. Smith J . Human Sir2 and the 'silencing' of p53 activity. Trends Cell Biol 2002; 12: 404–406.

    Article  CAS  Google Scholar 

  29. Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci USA 2003; 100: 10794–10799.

    Article  CAS  Google Scholar 

  30. Kamel C, Abrol M, Jardine K, He X, McBurney MW . SirT1 fails to affect p53-mediated biological functions. Aging Cell 2006; 5: 81–88.

    Article  CAS  Google Scholar 

  31. Ming M, Shea CR, Guo X, Li X, Soltani K, Han W et al. Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C. Proc Natl Acad Sci USA 107: 22623–22628.

    Article  CAS  Google Scholar 

  32. Fan W, Luo J . SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Mol Cell 39: 247–258.

    Article  CAS  Google Scholar 

  33. Jeong J, Juhn K, Lee H, Kim SH, Min BH, Lee KM et al. SIRT1 promotes DNA repair activity and deacetylation of Ku70. Exp Mol Med 2007; 39: 8–13.

    Article  CAS  Google Scholar 

  34. Yuan Z, Zhang X, Sengupta N, Lane WS, Seto E . SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol Cell 2007; 27: 149–162.

    Article  CAS  Google Scholar 

  35. Sugasawa K . Xeroderma pigmentosum genes: functions inside and outside DNA repair. Carcinogenesis 2008; 29: 455–465.

    Article  CAS  Google Scholar 

  36. Berg RJ, Ruven HJ, Sands AT, de Gruijl FR, Mullenders LH . Defective global genome repair in XPC mice is associated with skin cancer susceptibility but not with sensitivity to UVB induced erythema and edema. J Invest Dermatol 1998; 110: 405–409.

    Article  CAS  Google Scholar 

  37. Cheo DL, Meira LB, Burns DK, Reis AM, Issac T, Friedberg EC . Ultraviolet B radiation-induced skin cancer in mice defective in the Xpc, Trp53, and Apex (HAP1) genes: genotype-specific effects on cancer predisposition and pathology of tumors. Cancer Res 2000; 60: 1580–1584.

    CAS  PubMed  Google Scholar 

  38. Vousden KH, Lane DP . p53 in health and disease. Nat Rev Mol Cell Biol 2007; 8: 275–283.

    Article  CAS  Google Scholar 

  39. Solomon JM, Pasupuleti R, Xu L, McDonagh T, Curtis R, DiStefano PS et al. Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol 2006; 26: 28–38.

    Article  CAS  Google Scholar 

  40. Boily G, He XH, Pearce B, Jardine K, McBurney MW . SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene 2009; 28: 2882–2893.

    Article  CAS  Google Scholar 

  41. McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR et al. The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol 2003; 23: 38–54.

    Article  CAS  Google Scholar 

  42. Itoh T, Cado D, Kamide R, Linn S . DDB2 gene disruption leads to skin tumors and resistance to apoptosis after exposure to ultraviolet light but not a chemical carcinogen. Proc Natl Acad Sci USA 2004; 101: 2052–2057.

    Article  CAS  Google Scholar 

  43. Oka M, Edamatsu H, Kunisada M, Hu L, Takenaka N, Dien S et al. Enhancement of ultraviolet B-induced skin tumor development in phospholipase Cepsilon-knockout mice is associated with decreased cell death. Carcinogenesis 2010; 31: 1897–1902.

    Article  CAS  Google Scholar 

  44. Li H, Rajendran GK, Liu N, Ware C, Rubin BP, Gu Y . SirT1 modulates the estrogen-insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice. Breast Cancer Res 2007; 9: R1.

    Article  Google Scholar 

  45. Wu CL, Qiang L, Han W, Ming M, Viollet B, He YY . Role of AMPK in UVB-induced DNA damage repair and growth control. Oncogene 2013; 32: 2682–2689.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the NIH/NIEHS Grant ES016936 (to YYH), the American Cancer Society (ACS) Grant RSG-13-078-01 (to YYH), the University of Chicago Cancer Research Center (P30 CA014599), the CTSA (NIH UL1RR024999) and the University of Chicago Friends of Dermatology Endowment Fund. We thank Terri Li for Ki67 and TUNEL and XPC immunohistochemical analysis, and Dr Xiaobing Shi for kindly providing the WT and K382R mutant p53 plasmids.

Author information

Authors and Affiliations

  1. Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA

    M Ming, K Soltani, C R Shea & Y Y He

  2. Laboratory of Signal Transduction, NIEHS, National Institutes of Health, NC, USA

    X Li

Authors
  1. M Ming
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Soltani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C R Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Y He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Y He.

Ethics declarations

Competing interests

KS serves on the board of directors in Elorac Pharma and receives stocks from Elorac Pharma, DUSA, Winston and Gideon Pharmaceuticals, but none of them are relevant to this study. All the other 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

Cite this article

Ming, M., Soltani, K., Shea, C. et al. Dual role of SIRT1 in UVB-induced skin tumorigenesis. Oncogene 34, 357–363 (2015). https://doi.org/10.1038/onc.2013.583

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.583

Keywords

This article is cited by

Search

Advanced search

Quick links