Nuclear ßArrestin1 regulates androgen receptor function in castration resistant prostate cancer.

ABSTRACT

Progression of prostate cancer (PC) to terminal castration-resistant PC (CRPC) involves a diverse set of intermediates, and androgen receptor (AR) is the key mediator of PC initiation and progression to CRPC. Hence, identification of factors involved in the regulation of AR expression and function is a necessary first-step to improve disease outcome. In this study, we identified ubiquitous ßArrestin 1 (ßArr1) as a regulator of AR function in CRPC. Unbiased gene expression analysis of public datasets revealed increased levels of ARRB1 (the gene encoding ßArr1) in CRPC when compared to normal tissue. Further, ßArr1 expression correlated with enhanced AR transcriptional function in these datasets. The ßArr1 partitions to both nucleus and cytosol and mechanistic studies showed that nuclear, and not cytosolic, ßArr1 formed a complex with AR and AR-coregulator ßCatenin and that the heterotrimeric protein complex was recruited to androgen-response elements of AR-regulated genes. Functionally, we demonstrate that depletion of ßArr1 attenuates PC cell and tumor growth and metastasis, and rescued expression of nuclear, but not cytosolic, ßArr1 restores the PC colony growth and invasion of Matrigel in vitro and tumor growth and metastasis in mice. The targeting of ßArr1-regulated AR transcriptional function may be used in the development of new drugs to treat lethal CRPC.