Abstract 4986: Association of sirtuins and diet in cancer development: Studying the roles of SIRT2/3

Abstract

Abstract Lifestyle factors, especially diet, affects health and lifespan. Dietary restriction (DR) has been shown as a beneficial regimen to increase longevity and protect from cancer. On the other hand, high fat intake has been found to be associated with greater risk of several cancer types. In this regard, several studies suggest that the beneficial effect of calorie restriction (CR) is mediated by the increased activity of sirtuins, a family of NAD-dependent deacetylases that plays a role in aging and age-related diseases. However, the specific role of individual family members in the inhibitory role of CR in tumorigenesis has not been elucidated. With the exception of SIRT1, there is no evidence for the contribution of other sirtuins in the diet-induced effects on tumorigenesis. In this study, we investigated, for the first time, the role of SIRT2 and SIRT3, which are found predominantly in the cytoplasm and mitochondria respectively, in this context. To do this, Sirt2-/- and Sirt3-/- mice were crossed with p53-/- mice to generate: p53+/-, (Sirt2-/-; p53+/-), (Sirt3-/-; p53+/-), p53-/-, (Sirt2-/-; p53-/-), and (Sirt3-/-; p53-/-) mice. Subsequently, mice with the different genotypes were subjected to 3 dietary regimes; ad libitum control diet, 30% calorie restriction diet (CR), and high-fat diet (HFD). As expected, CR reduced tumor incidence and increased survival of mice wild type for both SIRT2 and SIRT3. In contrast, HFD significantly increased body weight, tumor incidence and decreased overall survival. Interestingly, the protective effect of CR was enhanced in (Sirt3-/-; p53-/-) compared to (Sirt3+/+; p53-/-) mice, as evidenced by delayed tumor incidence (median age 257 days vs 189 days) and increased survival. On the other hand, Sirt2 deletion in both p53+/- and p53-/- backgrounds abolished the protective effect of CR. In addition, loss of Sirt2 decreased tumor incidence age (111 days vs 184 days) and accelerated the death of p53 deficient mice on HFD. Our results highlight a new role of SIRT2 in mediating the diet-induced effect on tumorigenesis. Citation Format: Mohamed A. Ahmed, Carol O'Callaghan, Athanasios Vassilopulos. Association of sirtuins and diet in cancer development: Studying the roles of SIRT2/3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4986.