The exocrine pancreas can undergo acinar to ductal metaplasia (ADM). ADM occurs in pancreatitis and can generate precursor lesions of pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer. Sirtuin 1 (Sirt1), a NAD+ dependent protein deacetylase, is an important regulator in physiology and disease, including cancer.
We examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. mouse ADM models and established human PDAC cells. In addition, we analysed the expression of Sirt1’s key inhibitor Deleted in Breast Cancer 1 (Dbc1) and potential down stream targets.
Sirt1 is co-expressed with Dbc1 in nuclei of normal acinar cells. In ADM, Sirt1 but not Dbc1 undergoes a brief and transient cytoplasmic shuttling, suggestive of a temporary decreased nuclear and increased cytoplasmic Sirt1 activity. Our observations indicate that this contributes to the ADM process; Our results further underscore that two important regulators of acinar differentiation, i.e. the transcription factor Pancreatic transcription factor-1a (Ptf1a) and beta-Catenin can be deacetylated by Sirt1.
In addition to suppressive effects of a Sirtuin inhibitor on ADM, we also found that interference with Sirt1’s expression or application of a Sirtuin1/2 inhibitor in established PDAC tumours results in loss of cell viability. In PDAC, acetylation of beta-Catenin is not affected, unlike p53, a well characterised Sirt1 regulated protein in tumour cells.
This is the first study to show that Sirt1 is a critical regulator and potential therapeutic target throughout pancreatic carcinogenesis.