Sirtuin-1 regulates acinar to ductal metaplasia and supports cancer cell viability in pancreatic cancer

The exocrine pancreas can undergo acinar to ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD+-dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analysed the expression of KIAA1967, a key mediator of Sirt1 function, along with other potential Sirt1 downstream targets. Sirt1 was coexpressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear to cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, i.e. pancreatic transcription factor-1a and ß-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially down regulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of ß-catenin is not affected, unlike p53, a well characterised Sirt1 regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis. Sirt1 is co-expressed with Dbc1 in nuclei of normal pancreatic acinar cells. In ADM, Sirt1 undergoes a transient nuclear to cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important regulators of acinar differentiation, i.e. the transcription factor Pancreatic transcription factor-1a and beta-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. Dbc1 expression is differentially down regulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of beta-Catenin is not affected, unlike p53, a well characterised Sirt1 regulated protein in tumor cells. This is the first study to show that Sirt1 is an important regulator and potential therapeutic target throughout pancreatic carcinogenesis.

Publication year:2013

Keywords:pancreas, cancer