Sir2 is an evolutionary conserved protein deacetylase that in lower organisms has been shown to extend the lifespan when overexpressed and to mediate the effects of calorie restriction. In mammals, the situation is more complex due to the existence of seven Sir2 family members, Sirt1 being the closest mammalian homologue of Sir2. We have generated transgenic mice moderately overexpressing (2-3 fold) Sirt1 under its own regulatory elements (Sirt1-tg mice) to study its effect on mammalian metabolism, cancer and aging. We have found that Sirt1-tg mice are protected from the metabolic damage associated to high dietary fat intake due to a decreased inflammatory response[1]. Moreover, and contrary to what may have been expected, Sirt1-tg mice do not live longer, but they preserve a better health at old ages according to a variety of physiological indicators[2]. Regarding cancer, Sirt1 role is controversial, yet all the in vivo studies published so far support a tumor suppressor role for Sirt1. In our Sirt1-tg mice we have found that Sirt1 is able to protect from aging-associated spontaneous cancer development, as well as, from metabolic syndrome-associated liver cancer [2], and our results indicate that this beneficial effect of Sirt1 is due to its impact both on metabolism [1,2] and genomic integrity [2]. On the other hand, different genetic crosses of Sirt1-tg mice are helping us to further refine Sirt1 roles in cancer. Thus, we have found scenarios in which Sirt1 overexpression is able to accelerate tumorigenesis in certain tissues, which also show higher Sirt1 expression in human tumors, and this constitutes the first in vivo demonstration of an oncogenic role for Sirt1. I will present the latest data on Sirt1 and cancer, which suggest that Sirt1 plays a highly complex and tissue-specific role.

References:

1. Pfluger, P.T., Herranz, D., et al., (2008). Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A 105, 9793-9798.

2. Herranz, D. et al., (2010). Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 1:3, doi: 10.1038/ncomms1001

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY11-03. doi:10.1158/1538-7445.AM2011-SY11-03