α7 integrin is a critical co-regulator of chromatin accessibility and gene expression in HPV-negative head and neck cancer

Epigenetic regulation and gene transcription are dynamically modulated by extracellular signals, including focal adhesions; however, the role of integrins in these processes remains poorly understood. In this study in HPV-negative head and neck squamous cell carcinoma, we combined investigations in physiological 3-dimensional matrix cell models with multi-omics analyses, bioinformatics and artificial intelligence, to unmask the integrin effector signaling network that reshapes chromatin to drive cancer. Among the 12 α/β1 integrin receptors, α7 integrin emerged as the most potent modulator of histone post-translational modifications, associated with significant changes in gene transcription and chromatin accessibility. Mechanistically, phosphoproteomics revealed significant inhibition of MAPK- and PI3K/AKT-dependent signaling with concomitant functional impairment of cell cycling and cell survival upon ITGA7 depletion. In summary, these findings establish α7 integrin as a key co-regulator of chromatin accessibility and gene transcription in HPV-negative HNSCC, acting through an AURKA-centered axis that couples adhesion signaling to cell cycle control and patient survival, and nominate AURKA as an actionable therapeutic node downstream of the currently non-druggable ITGA7.