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HDAC3 mediates smoking-induced pancreatic cancer.

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journal contribution
posted on 02.08.2016 by Edderkaoui M, Xu S, Chheda C, Morvaridi S, Hu RW, Grippo PJ, Mascariñas E, Principe DR, Knudsen B, Xue J, Habtezion A, Uyeminami D, Pinkerton KE, Pandol SJ
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.

Funding

This work was supported by the NIAAA grant K01 AA019996 and the Hirshberg Foundation Award (to ME), the NCI grant P01CA163200, the NIAAA grant P50AA011999 and the Department of Veterans Affairs (to SJP).

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Publisher Statement

This is a copy of an article published in Oncotarget. © 2016 Impact Journals Publications. © The Author(s). http://www.impactjournals.com/oncotarget

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Impact Journals

Language

en_US

Issue date

16/02/2016

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