Tumor Biology

, Volume 37, Issue 5, pp 6429–6435 | Cite as

The expression levels of the sirtuins in patients with BCC

  • Metin Temel
  • Mustafa Nihat Koç
  • Saffet Ulutaş
  • Bülent Göğebakan
Original Article


Basal cell carcinoma (BCC) is the most common tumor in humans. Reduced expression of sirtuins interferes with DNA repair, which may cause mutations and genomic instability, and eventually leads to tumor development. In the present study, we investigate the expression levels of SIRT genes in non-tumoral and tumor tissues of patients with BCC. A total of 27 patients (16 males, 11 females) with BCC were included in the study; the mean age was 65.40 ± 10.74 years and mean follow-up was 2.5 ± 0.5 years. There were multiple synchronous lesions in six patients, and the remaining 21 patients had a single lesion. Tumor and non-tumoral tissue samples were collected from all patients, and mRNA expression levels of SIRT1–7 (Sirt1.1, Sirt1.2, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6, and Sirt7) were examined by real-time PCR. The results showed that expressions of SIRT1.1, SIRT1.2, SIRT4, SIRT5, SIRT6, and SIRT7 mRNAs were unchanged in tumor tissues of BCC patients compared with non-tumoral tissue samples. Importantly, the expressions of SIRT2 and SIRT3 mRNAs were significantly reduced in tumor tissue samples from BCC patients compared with non-tumoral tissues (P = 0.02 and P = 0.03, respectively). In light of the previous reports that have demonstrated a link between SIRT proteins and cancer, our findings suggest that SIRT2 and SIRT3 may plan important roles in BCC pathogenesis and could be candidate prognostic biomarkers for BCC.


BCC Sirtuin SIRT Cancer Lifespan Longevity 


Compliance with ethical standard

Conflicts of interest



This research did not receive funding from any agency in the public, commercial, or not for profit sectors.


  1. 1.
    Savoia P, Deboli T, Previgliano A, Broganelli P. Usefulness of photodynamic therapy as a possible therapeutic alternative in the treatment of basal cell carcinoma. Int J Mol Sci. 2015;16(10):23300–17. doi: 10.3390/ijms161023300.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Deng M, Marsch AF, Petronic-Rosic V. Basal cell carcinoma. Part 1: basal cell carcinoma has come of age. Skinmed. 2015;13(3):206–13. quiz 14.PubMedGoogle Scholar
  3. 3.
    Chu SW, Biswas A. Basal cell carcinomas showing histological features generally associated with cutaneous adnexal neoplasms. J Cutan Pathol. 2015. doi: 10.1111/cup.12577.Google Scholar
  4. 4.
    Gualdi G, Monari P, Apalla Z, Lallas A. Surgical treatment of basal cell carcinoma and squamous cell carcinoma. G Ital Dermatol Venereol. 2015;150(4):435–47.PubMedGoogle Scholar
  5. 5.
    Lewin JM, Carucci JA. Advances in the management of basal cell carcinoma. F1000Prime Rep. 2015;7:53. doi: 10.12703/P7-53.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403(6771):795–800. doi: 10.1038/35001622.CrossRefPubMedGoogle Scholar
  7. 7.
    Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 2012;13(4):225–38. doi: 10.1038/nrm3293.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hallows WC, Albaugh BN, Denu JM. Where in the cell is SIRT3?—functional localization of an NAD+-dependent protein deacetylase. Biochem J. 2008;411(2):e11–3. doi: 10.1042/BJ20080336.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell. 2005;16(10):4623–35. doi: 10.1091/mbc.E05-01-0033.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Longo VD, Kennedy BK. Sirtuins in aging and age-related disease. Cell. 2006;126(2):257–68. doi: 10.1016/j.cell.2006.07.002.CrossRefPubMedGoogle Scholar
  11. 11.
    Voelter-Mahlknecht S, Mahlknecht U. Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylases gene sirtuin 1. Int J Mol Med. 2006;17(1):59–67.PubMedGoogle Scholar
  12. 12.
    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(2):103–6. doi: 10.1007/s00403-006-0725-6.CrossRefPubMedGoogle Scholar
  13. 13.
    Saunders LR, Verdin E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene. 2007;26(37):5489–504. doi: 10.1038/sj.onc.1210616.CrossRefPubMedGoogle Scholar
  14. 14.
    Haigis MC, Guarente LP. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006;20(21):2913–21. doi: 10.1101/gad.1467506.CrossRefPubMedGoogle Scholar
  15. 15.
    Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J. 2007;404(1):1–13. doi: 10.1042/BJ20070140.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Poulose N, Raju R. Sirtuin regulation in aging and injury. Biochim Biophys Acta. 2015;1852(11):2442–55. doi: 10.1016/j.bbadis.2015.08.017.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Matsushima S, Sadoshima J. The role of sirtuins in cardiac disease. American journal of physiology Heart and circulatory physiology. 2015:ajpheart 00053 2015. doi: 10.1152/ajpheart.00053.2015.
  18. 18.
    Miyo M, Yamamoto H, Konno M, Colvin H, Nishida N, Koseki J, et al. Tumour-suppressive function of SIRT4 in human colorectal cancer. Br J Cancer. 2015;113(3):492–9. doi: 10.1038/bjc.2015.226.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sayd S, Thirant C, El-Habr EA, Lipecka J, Dubois LG, Bogeas A, et al. Sirtuin-2 activity is required for glioma stem cell proliferation arrest but not necrosis induced by resveratrol. Stem Cell Rev. 2014;10(1):103–13. doi: 10.1007/s12015-013-9465-0.CrossRefPubMedGoogle Scholar
  20. 20.
    Abdelmohsen K, Pullmann Jr R, Lal A, Kim HH, Galban S, Yang X, et al. Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Mol Cell. 2007;25(4):543–57. doi: 10.1016/j.molcel.2007.01.011.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Murayama A, Ohmori K, Fujimura A, Minami H, Yasuzawa-Tanaka K, Kuroda T, et al. Epigenetic control of rDNA loci in response to intracellular energy status. Cell. 2008;133(4):627–39. doi: 10.1016/j.cell.2008.03.030.CrossRefPubMedGoogle Scholar
  22. 22.
    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(2):137–48.CrossRefPubMedGoogle Scholar
  23. 23.
    Rajamohan SB, Pillai VB, Gupta M, Sundaresan NR, Birukov KG, Samant S, et al. SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1. Mol Cell Biol. 2009;29(15):4116–29. doi: 10.1128/MCB.00121-09.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yamamori T, DeRicco J, Naqvi A, Hoffman TA, Mattagajasingh I, Kasuno K, et al. SIRT1 deacetylates APE1 and regulates cellular base excision repair. Nucleic Acids Res. 2010;38(3):832–45. doi: 10.1093/nar/gkp1039.CrossRefPubMedGoogle Scholar
  25. 25.
    Noguchi A, Li X, Kubota A, Kikuchi K, Kameda Y, Zheng H, et al. SIRT1 expression is associated with good prognosis for head and neck squamous cell carcinoma patients. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(3):385–92. doi: 10.1016/j.oooo.2012.12.013.CrossRefPubMedGoogle Scholar
  26. 26.
    Wilking MJ, Singh C, Nihal M, Zhong W, Ahmad N. SIRT1 deacetylase is overexpressed in human melanoma and its small molecule inhibition imparts anti-proliferative response via p53 activation. Arch Biochem Biophys. 2014;563:94–100. doi: 10.1016/ Scholar
  27. 27.
    Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006;124(2):315–29. doi: 10.1016/j.cell.2005.11.044.CrossRefPubMedGoogle Scholar
  28. 28.
    Ford E, Voit R, Liszt G, Magin C, Grummt I, Guarente L. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 2006;20(9):1075–80. doi: 10.1101/gad.1399706.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    De Nigris F, Cerutti J, Morelli C, Califano D, Chiariotti L, Viglietto G, et al. Isolation of a SIR-like gene, SIR-T8, that is overexpressed in thyroid carcinoma cell lines and tissues. Br J Cancer. 2002;87(12):1479. doi: 10.1038/sj.bjc.6600636.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Frye R. “SIRT8” expressed in thyroid cancer is actually SIRT7. Br J Cancer. 2002;87(12):1479. doi: 10.1038/sj.bjc.6600635.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ashraf N, Zino S, Macintyre A, Kingsmore D, Payne AP, George WD, et al. Altered sirtuin expression is associated with node-positive breast cancer. Br J Cancer. 2006;95(8):1056–61. doi: 10.1038/sj.bjc.6603384.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Movahedi Naini S, Sheridan AM, Force T, Shah JV, Bonventre JV. Group IVA cytosolic phospholipase A2 regulates the G2-to-M transition by modulating the activity of tumor suppressor SIRT2. Mol Cell Biol. 2015;35(21):3768–84. doi: 10.1128/MCB.00184-15.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Guarente L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 2000;14(9):1021–6.PubMedGoogle Scholar
  34. 34.
    Kyrylenko S, Kyrylenko O, Suuronen T, Salminen A. Differential regulation of the Sir2 histone deacetylase gene family by inhibitors of class I and II histone deacetylases. Cell Mol Life Sci. 2003;60(9):1990–7. doi: 10.1007/s00018-003-3090-z.CrossRefPubMedGoogle Scholar
  35. 35.
    Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW. DNA repair, genome stability, and aging. Cell. 2005;120(4):497–512. doi: 10.1016/j.cell.2005.01.028.CrossRefPubMedGoogle Scholar
  36. 36.
    Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell. 2011;20(4):487–99. doi: 10.1016/j.ccr.2011.09.004.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6(1):1–6.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Aguissa-Toure AH, Wong RP, Li G. The ING family tumor suppressors: from structure to function. Cell Mol Life Sci. 2011;68(1):45–54. doi: 10.1007/s00018-010-0509-1.CrossRefPubMedGoogle Scholar
  39. 39.
    Kim SC, Sprung R, Chen Y, Xu Y, Ball H, Pei J, et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell. 2006;23(4):607–18. doi: 10.1016/j.molcel.2006.06.026.CrossRefPubMedGoogle Scholar
  40. 40.
    North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003;11(2):437–44.CrossRefPubMedGoogle Scholar
  41. 41.
    Rose G, Dato S, Altomare K, Bellizzi D, Garasto S, Greco V, et al. Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp Gerontol. 2003;38(10):1065–70.CrossRefPubMedGoogle Scholar
  42. 42.
    Glatt SJ, Chayavichitsilp P, Depp C, Schork NJ, Jeste DV. Successful aging: from phenotype to genotype. Biol Psychiatry. 2007;62(4):282–93. doi: 10.1016/j.biopsych.2006.09.015.CrossRefPubMedGoogle Scholar
  43. 43.
    Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120(4):483–95. doi: 10.1016/j.cell.2005.02.001.CrossRefPubMedGoogle Scholar
  44. 44.
    Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol. 2007;27(24):8807–14. doi: 10.1128/MCB.01636-07.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010;17(1):41–52. doi: 10.1016/j.ccr.2009.11.023.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell. 2011;19(3):416–28. doi: 10.1016/j.ccr.2011.02.014.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Bell EL, Emerling BM, Ricoult SJ, Guarente L. SirT3 suppresses hypoxia inducible factor 1alpha and tumor growth by inhibiting mitochondrial ROS production. Oncogene. 2011;30(26):2986–96. doi: 10.1038/onc.2011.37.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP. SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci U S A. 2002;99(21):13653–8. doi: 10.1073/pnas.222538099.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Schwer B, North BJ, Frye RA, Ott M, Verdin E. The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol. 2002;158(4):647–57. doi: 10.1083/jcb.200205057.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 2010;464(7285):121–5. doi: 10.1038/nature08778.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010;12(6):662–7. doi: 10.1016/j.cmet.2010.11.015.CrossRefPubMedGoogle Scholar
  52. 52.
    Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell. 2010;143(5):802–12. doi: 10.1016/j.cell.2010.10.002.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Chen IC, Chiang WF, Liu SY, Chen PF, Chiang HC. Role of SIRT3 in the regulation of redox balance during oral carcinogenesis. Mol Cancer. 2013;12:68. doi: 10.1186/1476-4598-12-68.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Quan Y, Wang N, Chen Q, Xu J, Cheng W, Di M et al. SIRT3 inhibits prostate cancer by destabilizing oncoprotein c-MYC through regulation of the PI3K/Akt pathway. Oncotarget. 2015.Google Scholar
  55. 55.
    Wang L, Wang WY, Cao LP. SIRT3 inhibits cell proliferation in human gastric cancer through down-regulation of Notch-1. Int J Clin Exp Med. 2015;8(4):5263–71.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Lesiak A, Sobolewska-Sztychny D, Majak P, Sobjanek M, Wodz K, Sygut KP, et al. Relation between sonic hedgehog pathway gene polymorphisms and basal cell carcinoma development in the Polish population. Arch Dermatol Res. 2015. doi: 10.1007/s00403-015-1612-9.PubMedGoogle Scholar
  57. 57.
    Morrow D, Cullen JP, Liu W, Guha S, Sweeney C, Birney YA, et al. Sonic Hedgehog induces Notch target gene expression in vascular smooth muscle cells via VEGF-A. Arterioscler Thromb Vasc Biol. 2009;29(7):1112–8. doi: 10.1161/ATVBAHA.109.186890.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Merico D, Isserlin R, Stueker O, Emili A, Bader GD. Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS One. 2010;5(11):e13984. doi: 10.1371/journal.pone.0013984.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    He S, He C, Yuan H, Xiong S, Xiao Z, Chen L. The SIRT 3 expression profile is associated with pathological and clinical outcomes in human breast cancer patients. Cell Physiol Biochem. 2014;34(6):2061–9. doi: 10.1159/000366401.CrossRefPubMedGoogle Scholar
  60. 60.
    Liu R, Fan M, Candas D, Qin L, Zhang X, Eldridge A, et al. CDK1-mediated SIRT3 activation enhances mitochondrial function and tumor radioresistance. Mol Cancer Ther. 2015;14(9):2090–102. doi: 10.1158/1535-7163.MCT-15-0017.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gonzalez Herrera KN, Lee J, Haigis MC. Intersections between mitochondrial sirtuin signaling and tumor cell metabolism. Crit Rev Biochem Mol Biol. 2015;50(3):242–55. doi: 10.3109/10409238.2015.1031879.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Metin Temel
    • 1
  • Mustafa Nihat Koç
    • 2
  • Saffet Ulutaş
    • 2
  • Bülent Göğebakan
    • 3
  1. 1.Department of Plastic and Reconstructive Surgery, School of MedicineMustafa Kemal UniversityHatayTurkey
  2. 2.Department of Plastic and Reconstructive Surgery, School of MedicineGaziantep UniversityGaziantepTurkey
  3. 3.Department of Medical Biology, School of MedicineMustafa Kemal UniversityHatayTurkey

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