RNA-seq of ITGA1, ITGA2, and TEAD1 knockout in prostate cell lines
The extracellular matrix (ECM) undergoes significant changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, we performed a meta-analysis of multiple PCa cohorts and dampened integrin signaling activation in disease progression. Further prioritization analysis revealed that downregulation or genomic loss of ITGA1 and ITGA2 integrin genes was associated with tumor progression to metastasis and prognosticated patient survival. 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 was induced by enhanced secretion and subsequent activation of autocrine TGFß1 and nuclear targeting of YAP1. Our 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 a1- and a2-integrins in vitro and in vivo. Remarkably, clinical data analysis revealed that TEAD1 downregulation or genomic loss was associated with aggressive PCa and could synergize with ITGA1 and ITGA2 expression to impact PCa prognosis and progression. Our study thus demonstrates that loss of a1- and a2-integrins, either via deletion/inactivation of the ITGA1/ITGA2 locus or via loss of TEAD1, contributes to PCa progression by inducing TGFß1-driven EMT.