Transcriptional Repression of Caveolin-1 gene Expression by Gata-6 in Bladder Smooth Muscle Hypertrophy in Mice and Humans

Abstract

Caveolin-1 is a structural and functional protein of caveolae that function as signaling platforms to mediate interaction between receptor proteins and adaptor and effector molecules to regulate signal generation, amplification, and diversification. Hypertrophied bladder smooth muscle (BSM) from the rabbit model of partial bladder outlet obstruction (PBOO) and men with benign prostatic hyperplasia (BPH)-induced PBOO shows a downregulation of Caveolin-1 and caveolar structural alteration. Here we report that caveolin-1 expression is diminished in PBOO-induced BSM hypertrophy in mice and in men with BPH. We characterized the proximal promoterof the human and mouse caveolin-1 gene and found that the transcriptionfactor GATA-6 binds this promoter, causing reduced expression of caveolin-1. Furthermore, we demonstrate that caveolin-1 expression levels inversely correlate with the abundance of GATA-6 in BSM hypertrophy in mice and humans. Importantly, silencing of GATA-6 gene expression up-regulates caveolin-1 expression, whereas overexpression of GATA-6 protein sustains the transcriptional repression of caveolin-1 in BSM cells. Together, our data suggest that GATA-6 acts as a transcriptional repressor of caveolin-1 gene expression in PBOO-induced BSM hypertrophy in men and mice. The GATA-6-induced transcriptional repression represents a new regulatory mechanism for caveolin-1 gene expression in pathologic BSM. Regulating the GATA-6 transcriptional regulation may serve as a target for new therapy for BPH-induced bladder dysfunction in aging men. Supported by O’Brien Urology Center Grant P50 DK052620