TEAD1 regulates ITGA1 and ITGA2 to control prostate cancer progression

Abstract

ABSTRACTThe 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 ofITGA1andITGA2integrin genes was associated with tumor progression to metastasis and poor prognosis in PCa patients. Genomic deletion of both α1- and α2-integrins activated epithelial-to-mesenchymal transition (EMT) in benign prostate epithelial cells, thereby enhancing their invasive potentialin vitroand converting them into tumorigenic cellsin vivo. Mechanistically, EMT was induced by enhanced secretion and subsequent activation of autocrine TGFβ1 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 ofITGA1andITGA2expression in PCa cells while TEAD1 loss phenocopied the dual loss of α2- and α2-integrins in vitro and in vivo. Notably, clinical data analysis revealed thatTEAD1downregulation or loss was associated with aggressive PCa and could synergize withITGA1andITGA2expression to impact PCa prognosis and progression. Altogether, our results demonstrate that loss of α1- and α2-integrins, either via deletion/inactivation of theITGA1/ITGA2locus or via loss ofTEAD1, contributes to PCa progression by inducing TGFβ1-driven EMT.