Dampened Regulatory Circuitry of TEAD1/ITGA1/ITGA2 Promotes TGF1 Signaling to Orchestrate Prostate Cancer Progression

The extracellular matrix (ECM) undergoes substantial changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, a meta-analysis of multiple PCa cohorts is performed which revealed that downregulation or genomic loss of ITGA1 and ITGA2 integrin genes is associated with tumor progression and worse prognosis. Genomic deletion of both ITGA1 and ITGA2 activated epithelial-to-mesenchymal transition (EMT) in benign prostate epithelial cells, thereby enhancing their invasive potential in vitro and converting them into tumorigenic cells in vivo. Mechanistically, EMT is induced by enhanced secretion and autocrine activation of TGF beta 1 and nuclear targeting of YAP1. An unbiased genome-wide co-expression analysis of large PCa cohort datasets identified the transcription factor TEAD1 as a key regulator of ITGA1 and ITGA2 expression in PCa cells while TEAD1 loss phenocopied the dual loss of alpha 1- and alpha 2-integrins in vitro and in vivo. Remarkably, clinical data analysis revealed that TEAD1 downregulation or genomic loss is associated with aggressive PCa and together with low ITGA1 and ITGA2 expression synergistically impacted PCa prognosis and progression. This study thus demonstrated that loss of alpha 1- and alpha 2-integrins, either via deletion/inactivation of the ITGA1/ITGA2 locus or via loss of TEAD1, contributes to PCa progression by inducing TGF beta 1-driven EMT. Cell-extracellular matrix interactions are critical regulators of cancer cell growth and invasion. This study revealed depletion of two collagen-binding receptors, alpha 1- and alpha 2-integrins, in aggressive forms of prostate cancer. Loss of alpha 1- and alpha 2-integrins triggered an autocrine secretion of TGF beta leading to EMT and elevated metastatic capacity. TEAD1 is identified as a key transcription factor regulating ITGA1 and ITGA2.image