Identification of βArrestin2 as a corepressor of androgen receptor signaling in prostate cancer

Androgen receptor (AR) signaling regulates the development and homeostasis of male reproductive organs, including the prostate. Deregulation of AR and AR coregulators, expression, or activity is involved in the initiation of prostate cancer and contributes to the transition of the disease to hormone-refractory stage. The ubiquitous βArrestin proteins are now recognized as bona fide adapters and signal transducers with target effectors found in both the cytosol and nucleus. Here, we provide evidence that βArrestin2 forms a complex with AR and acts as an AR corepressor in androgen-dependent prostate cancer cells. Accordingly, the forced overexpression of βArrestin2 diminishes, and knockdown of βArrestin2 expression with RNAi increases the androgen-induced prostate-specific antigen (PSA) gene expression. βArrestin2 serves as an adapter, bringing into close proximity the Mdm2 E3 ligase and AR, thereby promoting AR ubiquitylation and degradation. Human prostate tissues evidence an inverse relationship between the expression of βArrestin2 and AR activity: glands that express high levels of βArrestin2 exhibit low expression of PSA, and those glands that express low levels of βArrestin2 evidence elevated PSA levels. We conclude that βArrestin2 acts as a corepressor of AR by serving as a scaffold for Mdm2 leading to the AR ubiquitylation and degradation.