Abstract A73: Altered expression of sirtuin 1 and Deleted in Breast Cancer 1 and its functional impact on pancreatic carcinogenesis.

Abstract

Background and Aims: Sirtuin 1 (Sirt1) is an important regulator in physiology and disease, including cancer. This study investigated if Sirt1 and its inhibitor Deleted in Breast Cancer 1 (Dbc1) play a role in pancreatic carcinogenesis. Methods: Analyses were performed using normal exocrine pancreas, mouse models of acinar to ductal metaplasia (ADM) and human pancreatic ductal adenocarcinoma (PDAC) tissues and cell-lines. The expression of Dbc1 and Sirt1 was assessed in addition to the function of Sirt1, the effector protein. Results: Sirt1 and Dbc1 are coexpressed in acinar cell nuclei. Sirt1 undergoes a transient cytoplasmic shuttling in ADM, suggestive of an increase in Sirt1 activity. Inhibition of Sirt1’s shuttling or activity indeed restrains ADM and overexpression of Sirt1 partially induces ADM. Pancreatic transcription factor-1a (Ptf1a) and beta-Catenin, important regulators of acinar cell differentiation, were found to be targets of deacetylation by Sirt1. In PDAC tissue, Dbc1 has reduced expression that could also lead to increased Sirt1 effects. In addition, interference with Sirt1’s expression or function inhibits the growth of PDAC cells. Furthermore, the sensitivity of PDAC cells to the Sirt1 inhibitor Tenovin-6 is related to Sirt1/Dbc1 expression. Conclusions: This is the first study to show that Sirt1 plays a role in premalignant changes in acinar cell differentiation via effects on Ptf1a and beta-Catenin/Wnt signaling. It also demonstrates that Sirt1 is essential in established tumors and that reduced Dbc1 expression affects the sensitivity of PDAC cells for a Sirt1 drug. Together, this suggests that Dbc1/Sirt1 are potential therapeutic targets throughout the course of pancreatic carcinogenesis. Citation Format: Elke Wauters, Victor J. Sanchez-Arevalo Lobo, Andreia V. Pinho, Amanda Mawson, Luc Bouwens, Fransisco X. Real, Andrew V. Biankin, Ilse Rooman. Altered expression of sirtuin 1 and Deleted in Breast Cancer 1 and its functional impact on pancreatic carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A73.