Yuan Lin1, Jon Mallen-St Clair2, Guanyu Wang1, Jie Luo1, Fernando Palma-Diaz3, Chi Lai3, David A Elashoff4, Sherven Sharma5, Steven M Dubinett5, Maie St John6. 1. Lung Cancer Research Program of the Jonsson Comprehensive Cancer Center, United States; Division of Pulmonary and Critical Care Medicine, Department of Medicine, United States. 2. Department of Head and Neck Surgery, United States. 3. Department of Pathology and Laboratory Medicine, United States. 4. UCLA Head and Neck Cancer Program, United States. 5. Lung Cancer Research Program of the Jonsson Comprehensive Cancer Center, United States; Division of Pulmonary and Critical Care Medicine, Department of Medicine, United States; Department of Pathology and Laboratory Medicine, United States; Jonsson Comprehensive Cancer Center, United States; Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States. 6. Department of Head and Neck Surgery, United States; Jonsson Comprehensive Cancer Center, United States; UCLA Head and Neck Cancer Program, United States. Electronic address: mstjohn@mednet.ucla.edu.
Abstract
BACKGROUND: In the present study, we investigated the role of p38-p38IP signaling in the inflammation-induced promotion of epithelial-to-mesenchymal transition (EMT) in Head and Neck Squamous Cell Carcinoma (HNSCC). METHODS: Quantitative RT-PCR, western blot analysis, spheroid modeling and immunohistochemical staining of human HNSCC tissue sections were used. RESULTS: p38 inhibitor treated and p38 shRNA HNSCC cell lines demonstrate a significant upregulation in E-cadherin mRNA and a decrease in the mRNA expression of Snail. p38 binds to and stabilizes p38IP, a subunit of histone SPT3-TAF9-GCN5 acetyltransferase (STAGA), resulting in enhanced transcription of Snail. p38 shRNA HNSCC cell lines show a less invasive phenotype in a spheroid model. In clinical HNSCC samples, p38 interacting protein (p38IP) is significantly increased compared to adjacent normal tissue. An inverse relationship between p38, p38IP and E-cadherin is demonstrated. CONCLUSIONS: Herein we provide the first report that p38-p38IP is required for the Snail-induced E-cadherin down-regulation and cell invasion in HNSCC.
BACKGROUND: In the present study, we investigated the role of p38-p38IP signaling in the inflammation-induced promotion of epithelial-to-mesenchymal transition (EMT) in Head and Neck Squamous Cell Carcinoma (HNSCC). METHODS: Quantitative RT-PCR, western blot analysis, spheroid modeling and immunohistochemical staining of human HNSCC tissue sections were used. RESULTS:p38 inhibitor treated and p38 shRNA HNSCC cell lines demonstrate a significant upregulation in E-cadherin mRNA and a decrease in the mRNA expression of Snail. p38 binds to and stabilizes p38IP, a subunit of histone SPT3-TAF9-GCN5 acetyltransferase (STAGA), resulting in enhanced transcription of Snail. p38 shRNA HNSCC cell lines show a less invasive phenotype in a spheroid model. In clinical HNSCC samples, p38 interacting protein (p38IP) is significantly increased compared to adjacent normal tissue. An inverse relationship between p38, p38IP and E-cadherin is demonstrated. CONCLUSIONS: Herein we provide the first report that p38-p38IP is required for the Snail-induced E-cadherin down-regulation and cell invasion in HNSCC.
Authors: Amy R Dwyer; Carlos Perez Kerkvliet; Raisa I Krutilina; Hilaire C Playa; Tiffany N Seagroves; Carol A Lange; Deanna N Parke; Warner A Thomas; Branden A Smeester; Branden S Moriarity Journal: Mol Cancer Res Date: 2020-11-10 Impact factor: 6.333