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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, (HNSCC), we combined investigations in physiological three-dimensional, matrix-embedded cell models and patient-derived organoids 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 (ITGA7) emerged as the most potent modulator of histone post-translational modifications, associated with significant changes in gene transcription and chromatin accessibility. Depletion of ITGA7, achieved independently by CRISPR/Cas9 knockout and RNA interference, reduced chromatin accessibility at the AURKA locus and downregulated an AURKA-centered transcriptional program. 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. Across all analyses, machine-learning-based feature selection consistently nominated AURKA as the dominant downstream node, and tumor ITGA7 expression stratified patient overall survival in a non-linear manner. 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, potentially targetable with clinical Aurora-A inhibitors such as alisertib, as an actionable therapeutic node downstream of the currently non-druggable ITGA7.