Sirtainties in pancreatic cancer?

Sirtuin 1 (Sirt1) is a gene with diverse and complex roles in metabolic regulation, tumorigenesis and longevity, the latter being highly debated. Sirt1 is one of seven sirtuins that are NAD+ dependent and that, depending on the family member, modify histone and non-histone proteins by deacetylation and/or mono-ADP-ribosylation. Excellent reviews detail the long list of Sirt1 targets for deacetylation and capture its functions in homeostasis and disease [1, 2]. Recently, we reported a novel role for Sirt1 in pancreatic disease [3]. Until then, Sirt1 studies in the pancreas were confined to insulin producing endocrine cells. We investigated Sirt1 in the acinar cells of the pancreas that secrete digestive enzymes, and are prominent players in exocrine pancreatic disease. Acinar cells undergo ductal metaplasia when under stress, exemplified by the events in chronic pancreatitis where this can be a precursor to pancreatic ductal adenocarcinoma (PDAC) [4]. PDAC is the most prevalent form of pancreatic cancer and a lethal tumour that limits the median patient survival to less than 6 months after diagnosis. An increased understanding of pancreatic biology, both in pancreatitis and pancreatic cancer is warranted. Our work described Sirt1’s expression related to that of Ccar2 (Cell cycle and apoptosis regulator 2, also named Deleted in breast cancer 1 or KIAA1967), a protein that directly inhibits the deacetylation activity of Sirt1 (Figure 1). While in the unstressed pancreas both proteins colocalize in the nucleus, in acinar to ductal metaplasia Sirt1 temporary relocates to the cytoplasm while Ccar2 remains nuclear. This allows altered interaction of Sirt1 with its target genes, here, Pancreatic transcription factor 1a and beta-Catenin that critically regulate acinar cell differentiation and ductal metaplasia [4], and possibly other proteins. While SIRT1 is variably expressed in most of the human PDAC, CCAR2 is downregulated in a subset. These observations suggest that altered Sirt1 activity through changed intracellular localization and interaction with Ccar2 is important in different stages of pancreatic cancer development, revealing potential therapeutic opportunities. Indeed, Sirt1 inhibitors have generated excitement as therapeutic agents [1]. One of them, nicotinamide, attenuates the incidence of hepatocellular carcinoma without any evidence of toxic effects for the mice and is being tested in a clinical trial as a preventative agent for skin cancer. Our study showed that addition of nicotinamide partially repressed pancreatic acinar to ductal metaplasia. Other Sirt1 inhibitors, like Tenovin-6, showed anti-cancer effects in cell lines and mouse models, through activation of p53 and other mechanisms [1]. Another Sirt1 inhibitor (EX-527) is in clinical trial, albeit for Huntington’s Disease and not (yet) for cancer [1]. In our study, several PDAC cell lines were sensitive to Sirt1 inhibition, an observation that is extended by others who showed that Sirt1 inhibitors increase chemosensitivity of PDAC cells to the clinically applied drug gemcitabine [5, 6]. The latter data strongly suggest an oncogenic role of Sirt1 in late stage PDAC. Several Sirt1 mouse models are available to shed light on its potential contribution to PDAC development. The mouse models are based on impairment of Sirt1’s catalytic subunit through deletion of a critical exon or point mutation, and have been used in a whole body as well as in a tissue-restricted context [1, 2]. Complementary, a Sirt1 transgenic mouse has been widely studied [1, 2]. These mouse models, however, have illustrated the complexity of Sirt1 and have not uncommonly generated data that are hard to reconcile. One such example is the role in the intestine where both Sirt1 inactivation [7] and Sirt1 overexpression [1, 2] in the APC Min model of colorectal cancer led to reduced Editorial Material