Abstract 4113: α7 integrin is a critical co-regulator of chromatin accessibility and gene expression in HPV-negative head and neck cancer

Abstract Epigenetic regulation and gene transcription, which are mainly restricted to the nucleus, are dynamically modulated by extracellular signals. In HPV-negative head and neck squamous cell carcinoma (HNSCC), genetic mutations and epigenetic alterations promote a complex and heterogeneous tumor microenvironment, often characterized by extensive remodeling of the extracellular matrix. This process affects the expression and function of integrins, making integrins central signaling mediators and key regulators of cancer progression and therapy resistance. While the 12 heterodimeric α/β1 integrin receptors are known to be key factors for therapy resistance in various malignancies, their direct influence on chromatin accessibility and gene transcription remains to be elucidated. Here, we systematically investigated 24 HNSCC cell models physiologically cultured in a 3D matrix for nuclear morphology (3D super-resolution microscopy), whole exome sequencing, euchromatic and heterochromatic markers, transcriptome (RNA sequencing), DNA accessibility (ATAC sequencing), and phosphoproteome (protein microarrays). Integrative, multiomic bioinformatic analyses, including random forest algorithms, provided comprehensive insights into integrin-mediated epigenetic and transcriptomic regulation. The HNSCC model panel showed substantial variability in nuclear architecture and protein-altering mutations. An RNAi screen for all integrin receptors identified α7 integrin as the most potent modulator of the selected histone modification markers. Mechanistically, α7 integrin depletion increased spatial aggregation of nuclear DNA. RNA- and ATAC-seq showed that knockdown of α7 integrin alters the expression of 3, 257 genes, reducing chromatin accessibility at transcription start sites by 65%. This resulted in downregulation of genes involved in survival and chromatin regulation, while motifs for transcription factors such as JUN, FOSL1, and RELA were enriched in differentially accessible regions. Phosphoproteomics combined with artificial intelligence-based analyses showed significant inhibition of MAPK-dependent cell cycle progression, resulting in impaired proliferation, chromatin condensation, and reduced cell viability in all HNSCC models. In summary, this study provides substantial evidence that α7 integrin is an important co-regulator of gene transcription and chromatin accessibility. The discovery of the role of α7 integrin in these molecular mechanisms fundamentally supports the paradigm that cell adhesion dictates epigenetics and transcription. By increasing our understanding of these complex interactions, we may gain exploitable insights for the development of new, molecularly targeted drugs to treat patients with HNSCC. Citation Format: Olegs Borodins, Anne Vehlow, Nils Cordes. α7 integrin is a critical co-regulator of chromatin accessibility and gene expression in HPV-negative head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4113.