Abstract B44: The histone deacetylase SIRT6 regulates metabolism in pancreatic ductal adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death and one of the most aggressive and deadly malignancies, with limited therapeutic options. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that functions as a novel tumor suppressor, which regulates aerobic glycolysis in cancer cells. Whether glycolysis plays a role in pancreatic cancer development remains a topic of intense study. Importantly, we found SIRT6 to be downregulated in human PDAC and most pancreatic cancer cell lines, resulting in increased expression of glycolytic genes. To determine the role of SIRT6 in pancreatic cancer we utilized human PDAC cell lines that demonstrated low expression of SIRT6 compared to a human pancreatic ductal epithelial (HPDE) control cell line. Restoration of SIRT6 expression decreased the levels of glycolytic gene expression, reduced glucose uptake, and inhibited cell growth. Conversely, knockdown of SIRT6 in HPDE cells increased glycolytic gene expression, glucose uptake and enhanced cell growth. To further explore the role of SIRT6 in a genetically defined PDAC model, we used an autochthonous mouse model with conditional alleles for KRASG12D, p53, and SIRT6, together with a p48-Cre allele to delete SIRT6 and p53 while expressing oncogenic Ras exclusively in the pancreas. SIRT6null, KRASG12D, p53+/- p48 tumor cells also exhibited increased expression of glycolytic genes and had enhanced glucose uptake compared to SIRT6+/+, KRASG12D, p53+/- p48 tumor cells, a phenotype which is reversed by restoration of wild-type but not catalytically inactive SIRT6 expression. Understanding how SIRT6 regulates PDAC metabolism through the modulation of chromatin dynamics will hopefully lead to new therapies to tackle aberrant metabolism in this devastating disease. Citation Format: Sita Kugel, Carlos Sebastián, Rushika M. Perera, Nabeel Bardeesy, Raul Mostoslavsky. The histone deacetylase SIRT6 regulates metabolism in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B44.