HDAC3 mediates smoking-induced pancreatic cancer
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Mouad Edderkaoui1,2, Shiping Xu2,3, Chintan Chheda1, Susan Morvaridi1, Robert W. Hu1, Paul J. Grippo4,5, Emman Mascariñas4,5, Daniel R. Principe4,5, Beatrice Knudsen1, Jing Xue6, Aida Habtezion6, Dale Uyeminami7, Kent E. Pinkerton7, Stephen J. Pandol1,2
1Departments of Medicine and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
2Veterans Affairs Greater Los Angeles Healthcare System & University of California at Los Angeles, CA, USA
3Department of Gastroenterology, Nanlou Division, The PLA General Hospital, Beijing, China
4Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
5Department of Medicine, University of Illinois-Chicago, Chicago, IL, USA
6Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
7Center for Health and the Environment, University of California, Davis, CA, USA
Mouad Edderkaoui, e-mail: firstname.lastname@example.org
Keywords: smoking, HDAC, pancreatic cancer
Received: November 12, 2015 Accepted: December 22, 2015 Published: January 5, 2016
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.
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