SRF and CBP jointly regulate integrin β6 overexpression in head and neck squamous cell carcinomas

Abstract

Overexpression of integrin β6 (ITGB6) is crucially linked to the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC). The molecular mechanisms driving ITGB6 upregulation in HNSCC are not well understood. Our study comprehensively analyzed the transcriptional regulation and epigenetic modification mechanisms affecting ITGB6 transcription. We retrospectively evaluated ITGB6 expression using immunohistochemistry on a tissue microarray. Elevated ITGB6 expression in HNSCC specimens correlates with poor clinical prognosis. Using a luciferase reporter assay, site-directed mutagenesis, RNA interference, chromatin immunoprecipitation assay, and a 4-nitroquinoline 1-oxide (4NQO)-induced murine HNSCC model, we have demonstrated that the transcription factor Serum Response Factor (SRF) upregulates ITGB6 transcription. Our results further demonstrated that the histone acetyltransferase (HAT) CBP mediates the hyperacetylation of histones H3 and H4, facilitating their recruitment to the ITGB6 promoter. This recruitment strengthens SRF binding to the ITGB6 promoter. These findings suggest that SRF and CBP-mediated histone hyperacetylation are crucial for ITGB6 overexpression in HNSCC. Epigenetic mechanisms play a critical role in the active transcriptional expression of ITGB6 in HNSCC cells.