p38 MAPK mediates epithelial-mesenchymal transition by regulating p38IP and Snail in head and neck squamous cell carcinoma

•We document p38-dependent transcriptional regulation of E-cadherin in HNSCC.•Inhibition of p38 results in an increase in E-cadherin and decreases Snail transcription and leads to a less invasive cellular phenotype.•We demonstrate a reciprocal relationship between p38, p38IP and E-cadherin.•Therapies targeting the p38-p38IP pathway may diminish the propensity for tumor metastasis by blocking the subsequent activation of EMT via Snail.

SummaryBackgroundIn 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).MethodsQuantitative RT-PCR, western blot analysis, spheroid modeling and immunohistochemical staining of human HNSCC tissue sections were used.Resultsp38 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.ConclusionsHerein we provide the first report that p38-p38IP is required for the Snail-induced E-cadherin down-regulation and cell invasion in HNSCC.