¹Center for Cancer Therapeutics, Ottawa Health Research Institute, and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada

Correspondence: Dr MW McBurney, Centre for Cancer Therapeutics, Ottawa Health Research Institute, Box 926, 3rd Floor, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. E-mail: mmcburney@ohri.ca

Received 8 December 2008; Revised 24 February 2009; Accepted 16 April 2009; Published online 8 June 2009.

Abstract

The function of the class III histone deacetylase, Sir2, in promoting lifespan extension is well established in small model organisms. By analogy, SirT1, the mammalian orthologue of Sir2, is a candidate gene to slow down aging and forestall the onset of age-associated diseases. We have used SirT1-null mice to study the function of SirT1 in susceptibility to tumorigenesis. The number of intestinal polyps induced in mice carrying the Apc^min mutation was unaffected by the SirT1 genotype although the average polyp size was slightly smaller in the SirT1-null animals. Similarly, the presence or absence of SirT1 had no effect on incidence and tumor load of skin papillomas induced by the classical two-stage carcinogenesis protocol. We found that resveratrol topically applied to the skin profoundly reduced tumorigenesis. This chemoprotective effect was significantly reduced but not ablated in SirT1-null mice, suggesting that part of the protection afforded by resveratrol requires the SirT1-encoded protein. Thus, our results suggest that SirT1 does not behave like a classical tumor-suppressor gene but the antitumor activity of resveratrol is mediated at least in part by SirT1.