title: HDAC3 mediates smoking-induced pancreatic cancer.
abstract: Smoking is a major risk factor for developing pancreatic adenocarcinoma (PDAC); however, little is known about the mechanisms involved. Here we employed a genetic animal model of early stages of PDAC that overexpresses oncogenic Kras in the pancreas to investigate the mechanisms of smoking-induced promotion of the disease in vivo. We confirmed the regulation of the interactions between the tumor microenvironment cells using in vitro cellular systems. Aerial exposure to cigarette smoke stimulated development of pancreatic intraepithelial neaoplasia (PanIN) lesions associated with a tumor microenvironment-containing features of human PDAC including fibrosis, activated stellate cells, M2-macrophages and markers of epithelial-mesenchymal transition (EMT). The pro-cancer effects of smoking were prevented by Histone Deacetylase HDAC I/II inhibitor Saha. Smoking decreased histone acetylation associated with recruitment of and phenotypic changes in macrophages; which in turn, stimulated survival and induction of EMT of the pre-cancer and cancer cells. The interaction between the cancer cells and macrophages is mediated by IL-6 produced under the regulation of HDAC3 translocation to the nucleus in the cancer cells. Pharmacological and molecular inhibitions of HDAC3 decreased IL-6 levels in cancer cells. IL-6 stimulated the macrophage phenotype change through regulation of the IL-4 receptor level of the macrophage. This study demonstrates a novel pathway of interaction between cancer cells and tumor promoting macrophages involving HDAC3 and IL-6. It further demonstrates that targeting HDAC3 prevents progression of the disease and could provide a strategy for treating the disease considering that the HDAC inhibitor we used is FDA approved for a different disease.
authors.affiliation: Departments of Medicine and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Veterans Affairs Greater Los Angeles Healthcare System & University of California at Los Angeles, CA, USA.
authors.forename: Mouad
authors.initials: M
authors.lastname: Edderkaoui
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System & University of California at Los Angeles, CA, USA.|Department of Gastroenterology, Nanlou Division, The PLA General Hospital, Beijing, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Xu
authors.affiliation: Departments of Medicine and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Chintan
authors.initials: C
authors.lastname: Chheda
authors.affiliation: Departments of Medicine and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Morvaridi
authors.affiliation: Departments of Medicine and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Hu
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Department of Medicine, University of Illinois-Chicago, Chicago, IL, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Department of Medicine, University of Illinois-Chicago, Chicago, IL, USA.
authors.forename: Emman
authors.initials: E
authors.lastname: Mascariñas
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Department of Medicine, University of Illinois-Chicago, Chicago, IL, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Principe
authors.affiliation: Departments of Medicine and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Knudsen
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Aida
authors.initials: A
authors.lastname: Habtezion
authors.affiliation: Center for Health and the Environment, University of California, Davis, CA, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Uyeminami
authors.affiliation: Center for Health and the Environment, University of California, Davis, CA, USA.
authors.forename: Kent E
authors.initials: KE
authors.lastname: Pinkerton
authors.affiliation: Departments of Medicine and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Veterans Affairs Greater Los Angeles Healthcare System & University of California at Los Angeles, CA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
mesh_terms: D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D002278:Carcinoma in Situ / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D021441:Carcinoma, Pancreatic Ductal / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D012907:Smoking / Q000009:adverse effects*; D015534:Trans-Activators / Q000502:physiology; D000099186:Histone Deacetylase 3
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D015850:Interleukin-6; D015534:Trans-Activators; D000099186:Histone Deacetylase 3; C084010:pancreatic and duodenal homeobox 1 protein
keywords: HDAC; pancreatic cancer; smoking