The FKBP52 Cochaperone Acts in Synergy with [beta]-Catenin to Potentiate Androgen Receptor Signaling

• Published in: PloS one Vol. 10; no. 7
• Main Authors: Storer Samaniego, Cheryl, Suh, Ji Ho, Chattopadhyay, Arundhati, Olivares, Karen, Guy, Naihsuan, Sivils, Jeffrey C, Dey, Prasenjit, Yumoto, Fumiaki, Fletterick, Robert J, Strom, Anders M, Gustafsson, Jan-Åke, Webb, Paul, Cox, Marc B
• Format: Journal Article
• Language: English
• Published: Public Library of Science 24.07.2015
• Subjects: Androgens; Heat shock proteins; Hormones; Prostate cancer
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0134015

FKBP52 and [beta]-catenin have emerged in recent years as attractive targets for prostate cancer treatment. [beta]-catenin interacts directly with the androgen receptor (AR) and has been characterized as a co-activator of AR-mediated transcription. FKBP52 is a positive regulator of AR in cellular and whole animal models and is required for the development of androgen-dependent tissues. We previously characterized an AR inhibitor termed MJC13 that putatively targets the AR BF3 surface to specifically inhibit FKBP52-regulated AR signaling. Predictive modeling suggests that [beta]-catenin interacts with the AR hormone binding domain on a surface that overlaps with BF3. Here we demonstrate that FKBP52 and [beta]-catenin interact directly in vitro and act in concert to promote a synergistic up-regulation of both hormone-independent and -dependent AR signaling. Our data demonstrate that FKBP52 promotes [beta]-catenin interaction with AR and is required for [beta]-catenin co-activation of AR activity in prostate cancer cells. MJC13 effectively blocks [beta]-catenin interaction with the AR LBD and the synergistic up-regulation of AR by FKBP52 and [beta]-catenin. Our data suggest that co-regulation of AR by FKBP52 and [beta]-catenin does not require FKBP52 PPIase catalytic activity, nor FKBP52 binding to Hsp90. However, the FKBP52 proline-rich loop that overhangs the PPIase pocket is critical for synergy.