Sirtuin 1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions
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Andreia V. Pinho1,2,3, Amanda Mawson1,3, Anthony Gill1,3,4, Mehreen Arshi1, Max Warmerdam1, Marc Giry-Laterriere1,3, Nils Eling1, Triyana Lie1, Evelyne Kuster5, Simone Camargo5, Andrew V. Biankin1,2,3,6, Jianmin Wu1,2,3,7 Ilse Rooman1,2,3,8
1Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia
2St. Vincent’s Clinical School, UNSW Australia, Sydney, Australia
3The Australian Pancreatic Cancer Genome Initiative, Darlinghurst, Australia
4University of Sydney, Sydney, Australia
5University of Zürich, Zürich, Switzerland
6Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, Scotland
7Center for Cancer Bioinformatics, Peking University Cancer Hospital and Institute, Beijing, China
8Oncology Research Centre, Vrije Universiteit Brussel, Brussels, Belgium
Ilse Rooman, email: firstname.lastname@example.org
Keywords: pancreatic ductal adenocarcinoma, Sirtuin 1, tumorigenesis, proliferation, glycolysis
Received: November 27, 2015 Accepted: July 18, 2016 Published: August 02, 2016
Metabolic reprogramming is a feature of neoplasia and tumor growth. Sirtuin 1 (SIRT1) is a lysine deacetylase of multiple targets including metabolic regulators such as p53. SIRT1 regulates metaplasia in the pancreas. Nevertheless, it is unclear if SIRT1 affects the development of neoplastic lesions and whether metabolic gene expression is altered.
To assess neoplastic lesion development, mice with a pancreas-specific loss of Sirt1 (Pdx1-Cre;Sirt1-lox) were bred into a KrasG12D mutant background (KC) that predisposes to the development of pancreatic intra-epithelial neoplasia (PanIN) and ductal adenocarcinoma (PDAC). Similar grade PanIN lesions developed in KC and KC;Sirt1-lox mice but specifically early mucinous PanINs occupied 40% less area in the KC;Sirt1-lox line, attributed to reduced proliferation. This was accompanied by reduced expression of proteins in the glycolysis pathway, such as GLUT1 and GAPDH.
The stimulatory effect of SIRT1 on proliferation and glycolysis gene expression was confirmed in a human PDAC cell line. In resected PDAC samples, higher proliferation and expression of glycolysis genes correlated with poor patient survival. SIRT1 expression per se was not prognostic but low expression of Cell Cycle and Apoptosis Regulator 2 (CCAR2), a reported SIRT1 inhibitor, corresponded to poor patient survival.
These findings open perspectives for novel targeted therapies in pancreatic cancer.
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