TEAD1 regulates ITGA1 and ITGA2 to control prostate cancer progression

Abstract

The extracellular matrix (ECM) undergoes significant changes during prostate cancer (PCa) progression and actively regulates PCa growth and invasion. Here, we performed a meta-analysis of PCa cohorts and found that downregulation or loss of ITGA1 and ITGA2 integrin genes was associated with tumor progression to metastasis and poor prognosis in PCa patients. Genomic deletion of both 1- and 2-integrins 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 TGF{beta}1 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 2- and 2-integrins in vitro and in vivo. Notably, clinical data analysis revealed that TEAD1 downregulation or loss was associated with aggressive PCa and could synergize with ITGA1 and ITGA2 expression to impact PCa prognosis and progression. Altogether, our results demonstrate that loss of 1- and 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.