EMT plays an important role in cancer invasion and metastasis, during which epithelial cells lose their cell adhesive prop erties, repress E cadherin e pression, and increase their levels of mobility, matri metalloproteinases, and e pression of mesenchymal markers. E cadherin is a cell cell adhesion molecule e pressed predominantly by epithelial cells. Reduction or loss of E cadherin is considered a hallmark event of EMT, which initiates a series of signaling events and a major reorganization of the cell cytoskeleton. Concomitant with the loss of E cadherin and actin reorganization, cells undergoing EMT acquire a mesenchymal phenotype that becomes apparent by the e pression of mesenchymal cytoskeletal proteins such as vimentin, and increased deposition of e tracellular matri proteins by MMPs.

These e tracellu lar matri components stimulate integrin signaling and facilitate cell migration. Furthermore, decreased e pression of E cadherin during EMT is accompanied by increased e pression of N cadherin, which renders the cell more motile and invasive. These different events result in a loss of apical basal polarity, after which, the cells acquire a front back polarity that allows them to migrate in a directional fashion. The increased MMP e pression and activity allows the cells to degrade e tra cellular matri proteins, permitting their delamination and escape from their epithelial components. In cancer, epithelial tumor cells become more invasive after under going EMT, and enter the circulatory system through intravasation. This results in their dissemination to loci distal from the primary tumor.

Hence, elucidating the molecular mechanism which regulates e pression of E cadherin, N cadherin, and MMPs, has become pivotal for understanding cancer invasion and metastasis. Sirtuins are nicotinamide adenine dinucleotide dependent histone deacetylases. AV-951 Human homo logues of the Sir2 gene are found in yeast, and are considered a critical link to longevity, as they prolong the cellular replication cycles of Saccbaromyces Cerevi siae and Caenorbabditis elegans. Several types of sirtuin enzymes have been identified, and their enzymatic activities are regulated by the ratio of NAD to NADH. high NAD levels activate sirtuin enzymes, and conversely, high NADH levels inhibit their activity. Due to their abilities to deacetylate both histone and non histone substrates, sirtuin enzymes have roles in regulating multiple cellular and physiological processes, including diabetes, inflammation, neuro degenerative diseases, stress responses, cell survival, metabolism, aging, and longevity. Sirtuin enzymes are widely e pressed in normal tissues. SIRT1 localizes primarily in the nucleus, along with SIRT6 and SIRT7.