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.

Tobacco and alcohol as risk factors for pancreatic cancer

“…In these GEMMs, when nicotine is administered once PDAC is established, there is enhanced epithelial–mesenchymal transition (EMT) and a greater propensity to form hepatic metastases. Moreover, in KC mice, exposure to cigarette smoke promotes PanIN and stroma formation, EMT, and appearance of M2 macrophages, and these effects can be reversed by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), in agreement with the ability of cigarette smoke to decrease histone acetylation [41]. Taken together, the above studies support the concept that prolonged exposure to tobacco smoke over many years, as seen in humans, can lead to pancreatic malignant transformation.…”

Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis

“…Murine recombinant IL22 (rIL22) (100 ng/mouse, 5 times per week; Miltenyi Biotec, Bergisch Gladbach, Germany) or vehicle control was administrated intraperitoneally to mice at 4 weeks after first caerulein injection and mice were euthanized at 6 weeks. Pancreas from normal mice exposed to normal air or cigarette smoke for 6 h/ d for 7 weeks as described previously 15 were used for Western blot or qualitative reverse transcription polymerase chain reaction.…”

MRGBP as a potential biomarker for the malignancy of pancreatic ductal adenocarcinoma

“…MORF4-related gene-binding protein (MRGBP), which is also known as chromosome 20 open reading frame 20 (C20orf20), is identified as a protein capable of binding directly to MRG15 and MRGX proteins that are two indispensable components of tat-interacting protein 60 (TIP60) histone acetyltransferase (HAT) complex and histone deacetylases (HDACs) complexes [ 5 ]. The abnormally expressed TIP60/HAT complex and/or HDACs complexes have been shown to be associated with cell differentiation, proliferation, migration and invasion in diverse human cancers [ 6 – 8 ].…”