Abstract
Sirtuins are NAD+-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators.
Highlights
The mammalian sirtuin (SIRT) family, evolutionally conserved proteins belonging to class III histone deacetylases (HDACs), comprises seven members
An elegant fragment-based approach inspired by the structures of the SIRT inhibitors (SIRTi) suramin and nicotinamide recently identified a nanomolar SIRT2-selective inhibitor (21, Table 2), which is able to induce clear time-dependent and dose-dependent hyperacetylation of α-tubulin in MCF-7 cells and shows cytotoxic effects on some cancer cell lines [76]
A critical analysis of current knowledge and recent discoveries clearly indicates that SIRT modulation is beneficial against several diseases including cancer and neurodegeneration
Summary
The mammalian sirtuin (SIRT) family, evolutionally conserved proteins belonging to class III histone deacetylases (HDACs), comprises seven members. Identified in 2006, cambinol (6, Table 2) is a moderate SIRT1/2i that induces hyperacetylation of p53, α-tubulin, FOXO3a, and Ku70 in NCI-H460 and HeLa cancer cells; promotes apoptosis in BCL-6-expressing Burkitt lymphoma cells; and reduces tumor growth in a xenograft model [50].
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