Figure 6.
SIRT1 plays key roles in cell survival and apoptosis. The complexity of SIRT1 regulation has made it a challenge to decipher SIRT1’s role in cancer. The SIRT1 gene is under the control of both environmental stimuli such as fasting and exercise and microRNAs (miRNAs), tenovins, and the hypermethylated in cancer 1 (HIC1) transcriptional repressor. The SIRT1 enzyme can also be modulated by protein-protein interactions with deleted in breast cancer 1 (DBC1), adaptor response to oxidative stress (AROS), Dif1, and necdin. SIRT1 interacts with and deacetylates numerous proteins involved in cell survival, DNA repair, and apoptosis (Figure 3). On the basis of this information, it has been difficult to predict what SIRT1 overexpression or activation by SIRT1-activating compounds will do in vivo, but so far experiments (171) point to SIRT1 acting as a tumor suppressor in the case of the p53−/+, breast cancer 1 (BRCA1), 7,12-dimethylbenz[α]anthracene (DMBA), and APCmin+/− models of lymphoma, breast, skin, and colon cancers, respectively. Abbreviations: CR, calorie restriction; DBC1, deleted in breast cancer 1; FOXO, forkhead box, subgroup O; HIC1, hypermethylated in cancer 1; NF-κB, nuclear factor kappa B.