SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

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.

Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis

“…21 However, no notable tumor formation has been reported in 2 aging studies using SIRT1 Ϫ/Ϫ mice over 18-24 months 48,49 and SIRT1 homozygous knockout does not increase intestinal polyp load in Apc min/ϩ mice. 50 Given the results of the present study, it is likely that tissue types may influence SIRT1 functions in cancer. Nevertheless, our study reveals SIRT1 activation as a novel mechanism for CML cell proliferation and survival, …”

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

“…First, SIRT1 overexpression is shown to suppress intestinal polyp formation in Apc min/ þ mice (Firestein et al, 2008), Nicotinamide phosphoribosyltransferase and prostate cancer B Wang et al suggesting a tumor suppressor function. In contrast, the SIRT1 homozygous knockout fails to increase intestinal polyp load in Apc min/ þ mice (Boily et al, 2009). Second, Oberdoerffer et al (2008) show that SIRT1 overexpression or resveratrol treatment reduces thymic lymphoma in p53 þ /À background.…”

“…Wang et al also suggest that SIRT1 is a haploinsufficient tumor suppressor (Wang et al, 2008). However, no notable tumor formation has been reported in two aging studies using SIRT1 À/À mice over 18 to 24 months (Boily et al, 2008;Li et al, 2008) and SIRT1 homozygous knockout does not increase intestinal tumors in Apc min/ þ mice (Boily et al, 2009). Therefore, more in vivo studies are needed for comprehensive understanding of roles of SIRT1 in cancer.…”

Sirtuins at a glance

“…In addition, overexpression of SIRT1 in murine intestines reduces the incidence of cancer and growth in a mouse colon cancer model: SIRT1 was shown to deacetylate -catenin and inhibit its accumulation in the nucleus, which lead to the hyperactivation of -catenin and the formation of tumors (Firestein et al, 2008). Another study showed that the SIRT1 activator resveratrol also protects mice that are heterozygous for p53 from cancer (Boily et al, 2009;Oberdoerffer et al, 2008). Consistent with these results, it was shown that SIRT1 haploinsufficiency facilitates tumorigenesis in these mice by accelerating tumorigenesis (Wang et al, 2008).…”