Abstract
SIRT1 is a mammalian NAD+-dependent histone deacetylase implicated in metabolism, development, aging and tumorigenesis. Prior studies that examined the effect of enterocyte-specific overexpression and global deletion of SIRT1 on polyp formation in the intestines of APC+/min mice, a commonly used model for intestinal tumorigenesis, yielded conflicting results, supporting either tumor-suppressive or tumor-promoting roles for SIRT1, respectively. In order to resolve the controversy emerging from these prior in vivo studies, in the present report we examined the effect of SIRT1 deficiency confined to the intestines, avoiding the systemic perturbations such as growth retardation seen with global SIRT1 deletion. We crossed APC+/min mice with mice bearing enterocyte-specific inactivation of SIRT1 and examined polyp development in the progeny. We found that SIRT1-inactivation reduced total polyp surface (9.3 mm2 vs. 23.3 mm2, p = 0.01), average polyp size (0.24 mm2 vs. 0.51 mm2, p = 0.005) and the number of polyps >0.5 mm in diameter (14 vs. 23, p = 0.04), indicating that SIRT1 affects both the number and size of tumors. Additionally, tumors in SIRT1-deficient mice exhibited markedly increased numbers of cells undergoing apoptosis, suggesting that SIRT1 contributes to tumor growth by enabling survival of tumor cells. Our results indicate that SIRT1 acts as a tumor promoter in the APC+/min mouse model of intestinal tumorigenesis.
Highlights
SIRT1 is a mammalian NAD+-dependent histone deacetylase that plays important roles in ageing, metabolism, development, neurodegeneration and tumorigenesis
When we compared tumor size distribution between SIRT12/2 and SIRT1+/+ mice we found that only 2% of adenomas in SIRT12/2 mice were larger than 1.0 mm in diameter, whereas 12% of tumors in the control group reached this size (p = 0.0076)
In order to bypass systemic effects related to global deletion of SIRT1, especially those associated with reduced circulatory levels of Insulin-like Growth Factor 1 (IGF-1), and focus instead on its intestine-specific role only, we generated APC+/min mice harboring enterocyte-specific inactivation of SIRT1 and examined their susceptibility to forming intestinal polyps
Summary
SIRT1 is a mammalian NAD+-dependent histone deacetylase that plays important roles in ageing, metabolism, development, neurodegeneration and tumorigenesis (reviewed in [1,2,3,4,5,6]). SIRT1 was first implicated in tumorigenesis by the finding that it deacetylates and down-regulates the tumor suppressor p53 under conditions of genotoxic stress, decreasing its pro-apoptotic activity and promoting survival of cells that have accumulated DNA damage [9,10]. SIRT1 was later found to deacetylate and regulate several other proteins that share similar roles in cellular stress responses (e.g. Ku70, p73, FoxO3a, FoxO4 and E2F1[13,14,15,16,17]), while small-molecule inhibitors of SIRT1 were shown to exhibit antitumor activity, suggesting that pharmacological inhibition of SIRT1 could be therapeutically beneficial in a subset of human cancers [18,19,20,21,22,23]. Coupled with the observation that SIRT1 expression levels are increased in many human tumors (e.g. colon cancer) and usually associated with poor prognosis in these patients [25,26,27,28,29,30,31], these findings suggest that SIRT1 acts as a tumor promoter
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