title: Sirtuin 1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions.
abstract: 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.
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.|St. Vincent's Clinical School, UNSW Australia, Sydney, Australia.|The Australian Pancreatic Cancer Genome Initiative, Darlinghurst, Australia.
authors: Andreia V
authors: AV
authors: Pinho
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.|The Australian Pancreatic Cancer Genome Initiative, Darlinghurst, Australia.
authors: Amanda
authors: A
authors: Mawson
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.|The Australian Pancreatic Cancer Genome Initiative, Darlinghurst, Australia.|University of Sydney, Sydney, Australia.
authors: Anthony
authors: A
authors: Gill
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.
authors: Mehreen
authors: M
authors: Arshi
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.
authors: Max
authors: M
authors: Warmerdam
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.|The Australian Pancreatic Cancer Genome Initiative, Darlinghurst, Australia.
authors: Marc
authors: M
authors: Giry-Laterriere
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.
authors: Nils
authors: N
authors: Eling
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.
authors: Triyana
authors: T
authors: Lie
authors: University of Zürich, Zürich, Switzerland.
authors: Evelyne
authors: E
authors: Kuster
authors: University of Zürich, Zürich, Switzerland.
authors: Simone
authors: S
authors: Camargo
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.|St. Vincent's Clinical School, UNSW Australia, Sydney, Australia.|The Australian Pancreatic Cancer Genome Initiative, Darlinghurst, Australia.|Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, Scotland.
authors: Andrew V
authors: AV
authors: Biankin
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.|St. Vincent's Clinical School, UNSW Australia, Sydney, Australia.|The Australian Pancreatic Cancer Genome Initiative, Darlinghurst, Australia.|Center for Cancer Bioinformatics, Peking University Cancer Hospital and Institute, Beijing, China.
authors: Jianmin
authors: J
authors: Wu
authors: Cancer Division, The Garvan Institute of Medical Research, Sydney, Australia.|St. Vincent's Clinical School, UNSW Australia, Sydney, Australia.|The Australian Pancreatic Cancer Genome Initiative, Darlinghurst, Australia.|Oncology Research Centre, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Ilse
authors: I
authors: Rooman
mesh_terms: D000818:Animals; D002278:Carcinoma in Situ; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D056564:Sirtuin 1; D005947:Glucose
keywords: Sirtuin 1; glycolysis; pancreatic ductal adenocarcinoma; proliferation; tumorigenesis