Abstract 2735: Targeting HDAC prevents smoking-induced pancreatic cancer metastasis

Abstract

Abstract Background: Cigarette smoking is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Among patients with metastatic PDAC, 90% have liver and 50% have lung metastasis. In this project we investigated the effect of smoking on pancreatic cancer invasion and metastasis in vitro and in vivo. Methods: Pancreatic cancer cells were treated with different doses of 4-(methylnitro-s-amino)-1-(3-pyridyl)-1-butanone (NNK) and cigarette smoke extract (CSE) and cancer cell survival, markers of epithelial to mesenchymal transition (EMT) as well as invasion were measured by MTT assay, Western, RT-PCR and Matrigel Invasion Assay. In a syngeneic mouse model of pancreatic cancer mice were pre-treated with NNK for 4 weeks and mouse cancer cells were injected in the spleen of mice. Progression of the disease including metastasis to liver and lung was monitored by imaging and tissues were collected and analyzed after 6 weeks. Results: Smoking compounds slightly but significantly increased cancer cell survival. They significantly promoted expression of EMT markers and promoted invasion of the cancer cells. Inhibition of histone deacetylase (HDAC) (class I and II), and especially HDAC4, prevented the pro-EMT and invasion effect of smoking compounds. NNK increased the protein level of HDAC4 and the level of Yes-associated protein 1 (Yap) translocated to the nucleus. Inhibition of HDAC4 reversed this effect. Analysis of Yap binding proteins showed presence of HDAC4 in the Yap protein complex. HDAC inhibition decreased the level of Yap-HDAC4 complex formation. In vivo, NNK promoted metastasis of pancreatic cancer cells to mice lung and liver; whereas, inhibition of HDAC decreased the number of metastases to a level lower than control treated mice. Smoking promoted liver and lung fibrosis and inflammation and measured by the level of collagen staining, stellate cells activation and immune cells staining. HDAC inhibition reversed these effects of smoking. Conclusion: We showed for the first time in an animal model that smoking promotes metastasis of PDAC to the lung. We found that HDAC4 is key mediator of this effect. Inhibiting HDAC4 is a promising strategy for preventing PDAC metastasis. Citation Format: Jiyong Yang, Chintan Chheda, Dina Hauptschein, Latifa Zayou, Josiah Tang, Qiang Wang, Stephen J. Pandol, Mouad Edderkaoui. Targeting HDAC prevents smoking-induced pancreatic cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2735.