Abstract B40: Oncogenic Kras induces histone acetylation in pancreatic ductal adenocarcinoma

Abstract

Abstract Deregulation of cellular epigenetics is essential for malignant transformation. However, the mechanisms that cause epigenetic alterations in cancer cells are incompletely understood. Recent evidence has shown that cellular metabolism has a direct impact on the epigenome, since many chromatin-modifying enzymes rely on intracellular metabolites as cofactors or donor substrates. We have previously shown that the metabolic enzyme ATP-citrate lyase (ACLY), which generates nuclear-cytoplasmic acetyl-CoA from glucose, is required for maintaining histone acetylation levels in multiple mammalian cell types, suggesting that alterations in acetyl-CoA metabolism in cancer cells might also impact histone acetylation levels. Cellular metabolism is massively rewired in multiple cancer types, including pancreatic cancer, although the impact of metabolic alterations on the tumor epigenome is poorly understood. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl-CoA availability mediated by oncogenic metabolic reprogramming. In this study, we demonstrate that acetyl-CoA abundance in cancer cells is dynamically regulated by glucose availability and that histone acetylation levels are responsive to the ratio of acetyl-CoA:coenzyme A within the nucleus. To test whether oncogene activation could mediate changes in histone acetylation in vivo, we performed immunohistochemical analysis comparing pancreata from mice expressing KrasG12D with those from mice with WT Kras. Whereas the acinar cells of WT mice exhibited very low levels of histone H4 (K5/8/12/16) acetylation, in KPC (LSL-KrasG12D; p53L/+; Pdx1-Cre) mice, acinar H4 acetylation was markedly increased, prior to the appearance of histological abnormalities or aberrant cell proliferation. High H4 acetylation persisted in pancreatic intraepithelial neoplasia (PanIN) and PDA. Histone acetylation in PanIN-derived primary cells was selectively impaired by PI3K and Akt inhibitors, correlating with suppression of glucose consumption and cellular acetyl-CoA levels. Moreover, addition of supraphysiological doses of acetate, a source of acetyl-CoA alternative to glucose, restored histone acetylation levels. These data suggest that oncogenic Kras promotes elevated histone acetylation preceding tumor development through Akt-dependent regulation of cellular acetyl-CoA levels. Further mechanistic analysis suggests that Akt promotes elevated histone acetylation through combined effects on promoting glucose uptake and phosphorylation and activation of ATP-citrate lyase, a metabolic enzyme that produces nuclear-cytoplasmic acetyl-CoA. The aberrant activation of the PI3K/Akt pathway occurs in broad variety of human malignancies. pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors, suggesting that PI3K-Akt-dependent promotion of acetyl-CoA metabolism may contribute to histone acetylation levels in multiple cancer types. Our data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in tumors and offer novel insights on Kras-induced pancreatic carcinogenesis. Citation Format: Alessandro Carrer, Joyce V. Lee, Supriya Shah, Nathaniel W. Snyder, Ellen Jackson, Nicole M. Aiello, Benjamin A. Garcia, Lewis A. Chodosh, Ben Z. Stanger, Ian A. Blair, Kathryn E. Wellen. Oncogenic Kras induces histone acetylation 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 B40.