Adult pancreatic acinar cells can dedifferentiate and gain metaplastic ductal characteristics, referred to as acinar to ductal metaplasia (ADM). ADM occurs in pancreatitis and can generate precursor lesions of pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic tumour. Understanding the molecular pathology of ADM and PDAC can inform innovative chemoprevention and therapeutic strategies.
Sirtuin 1 (Sirt1), the founding member of NAD+ deacetylases, is an important regulator in physiology and disease, including cancer. We examined the expression and the role of Sirt1 in mouse ADM models and in established human PDAC tumours. In addition, we analysed Sirt1 target proteins and the effects of Sirt1 inhibitors in these models.
We showed that Sirt1 is co-expressed with its key inhibitor Deleted in Breast Cancer 1 (Dbc1) in nuclei of differentiated acinar cells. In ADM, Sirt1 undergoes a transient cytoplasmic shuttling. Inhibition of this shuttling restrains induction of Krt19 expression, a hallmark of ADM. A similar effect with additional preservation of acinar differentiation markers was obtained by application of Nicotinamide, a natural inhibitor of Sirt1. Overexpression of Sirt1, on the other hand, partially suppressed acinar differentiation. We further demonstrated that Sirt1 could deacetylate the master transcription factor of acinar differentiation Pancreatic transcription factor-1a (Ptf1a). Deacetylation of beta-Catenin, a known Sirt1 target, and altered beta-Catenin/Wnt signalling occurs in parallel with Sirt1 changes in ADM.
Sirt1 is also expressed in pancreatic cancer cells and interference with its expression or application of the Sirt1 inhibitor Tenovin-6 results in loss of PDAC cell viability. Furthermore, the sensitivity of a panel of PDAC cell lines to Tenovin-6 correlates with Sirt1/Dbc1 expression.
This is the first study that demonstrates the essential role of Sirt1 in the loss of pancreatic acinar cell differentiation and in tumour maintenance, revealing that Sirt1 is a potential therapeutic target throughout the course of pancreatic carcinogenesis.