Interest in sirtuins has grown in the last decade, mainly because of their critical role in different biological processes, such as regulation of gene expression, control of metabolic processes, apoptosis and cell survival, DNA repair, development, neuro-protection, and inflammation. Sirtuins control many vital functions and are involved in several pathologies such as metabolic diseases, neurodegenerative disorders, and cancer.
SirT1 has been shown to be significantly up-regulated in different types of cancer including acute myeloid leukemia (AML), prostate, colon, and skin cancers.
Given that only SirT1 and SirT2 seem to control levels of H4K16 acetylation in many settings, and that only SirT1 is proven to be altered in certain cancers, H4K16ac loss in cancer has been correlated with SirT1 deregulated activity.
Nevertheless, SirT1 seems to play contradictory roles, both as tumor suppressor or tumor promoter (Deng, 2009
; Bosch-Presegue and Vaquero, 2011
). The initial evidence that SirT1 acts as tumor promoter derives from its repressive effect on tumor suppressor p53 (Deng, 2009
). By interacting physically with p53, SirT1 blocks its functions through deacetylation at the C-terminal K382 residue (Vaziri et al., 2001
). Moreover, SirT1 overexpression in cancer represses p53-dependent cell-cycle arrest and apoptosis in response to DNA damage and oxidative stress. DNA damage-induced acetylation of p53 leads to its activation. In response to damage, SirT1 binds to and deacetylates p53, thus reducing its functional and transcriptional activities. Overexpression of SirT1 disrupts p53-dependent pathways, resulting in a significant reduction in the cell’s ability to respond to stress and DNA damage. In contrast, the inhibition of SirT1 potentiates p53-dependent apoptosis (Deng, 2009
; Rahman and Islam, 2011
). These findings underline the involvement of SirT1 in tumorigenesis, given that SirT1 overexpression may increase the risk of cancer in mammals by inhibiting p53 and potentially other tumor suppressor genes, including FOXO family members, p73, Rb, and several others.
In contrast, several studies have suggested that SirT1 also has a tumor suppressor role. Decreased SirT1 levels have been reported for glioma, bladder, prostate, and ovarian cancers. Furthermore, some studies have suggested that SirT1 overexpression in APC−/+
mice reduces rather than increases colon cancer formation (Firestein et al., 2008
). This action seems to be caused by SirT1 deacetylation of β-catenin, which promotes cytoplasmic localization of the nuclear-localized oncogenic form of β-catenin. In addition, in SirT1-deficient mice, embryos die at middle gestation stages, displaying increased acetylation of H3K9 and H4K16, reduced chromosome condensation and aberrant mitosis (Firestein et al., 2008
; Deng, 2009
). SirT1 deficiency also causes reduced DNA double-strand break repair and radiation sensitivity (Wang et al., 2008
). It has also been suggested that SirT1 plays a role as tumor suppressor by regulating c-Myc. c-Myc binds to and induces SirT1. This interaction results in decreased c-Myc stability, compromising its transformational capability. These data provide strong evidence for a tumor suppressor role of SirT1 in these settings. Importantly, it still seems possible that the expression level and activity of SirT1 may modulate a delicate balance between suppression and promotion of oncogenesis, thus displaying dual dependence on its spatial and temporal distribution and stage of tumorigenesis (Bosch-Presegue and Vaquero, 2011
). A potential tumor suppressor role has also been proposed for the other human sirtuins (McGuinness et al., 2011
). This hypothesis is supported by several findings such as the reduction of SirT2 in a large number of human brain tumor cell lines, and its involvement in cell-cycle progression. SirT3 is the only mitochondrial sirtuin implicated in tumorigenesis. Its reduction in several cancers leads to an increase in ROS (reactive oxygen species) production, which results in enhanced tumor growth (Kim et al., 2010
). SirT5 overexpression has been found in a study of pancreatic cancer (Ouaïssi et al., 2008
). Recently, a role for SirT6 and SirT7 in tumorigenesis has also been proposed. SirT6 might be involved as a result of its control of the NFκB pathway and DNA double-strand repair. SirT7, whose expression inversely correlates with the tumorigenic potential in several murine cell lines (Vakhrusheva et al., 2008
), displays increased expression levels in breast cancer (Ashraf et al., 2006
Following these rationals, tumors with deregulated expression or function of sirtuins may benefit from an approach based on the use of SirT inhibitors.