Abstract 3253: Id4 and FKBP52 interaction regulates androgen receptor activity in normal prostate and prostate cancer

Abstract

Abstract The androgen receptor (AR) is a ligand activated transcription factor and important member of the steroid hormone nuclear receptors. Androgen signaling through AR plays a critical role in prostate tumorigenesis. AR transcriptional enhancement normally requires FKBP52 mediated peptidyl-prolyl cis-trans isomerase (PPIase) activity as well as HSP90-binding ability. FK506 binding protein 4 (FKBP52) is an AR folding factor that has critically important physiological roles in male reproductive tissues. Despite several experimental evidences, the molecular mechanism by which FKBP52 promotes AR signaling in prostate cancer still remains to be investigated. Our previous lab studies have demonstrated that Id4 is regulated by androgens in normal prostate epithelial and LNCaP cells. However, the interaction of Id4 and with the androgen receptor pathway in regulating the development and function of the normal prostate still remains elusive. Here we demonstrate that Id4 (inhibitor of differentiation-4) a dominant negative regulator of bHLH transcription factors can physically interact with AR, FKBP52 and HSP90 in early stage prostate cancer LNCaP cells and thereby selectively regulating AR transcriptional activity. Id4 is highly expressed in the normal prostate and decreased in prostate cancer due to promoter hypermethylation. Loss of Id4 in LNCaP cells resulted in ligand independent AR activation characterized by increased AR nuclear translocation and expression of PSA, FKBP51, FKBP52 and ARD1, the transcriptional targets of AR. Differential protein expression between LNCaP and LNCaP-Id4 demonstrated that loss of Id4 cells significantly elevated the levels of FBKP52 and Hsp27, the two known transcriptional regulators and nuclear transporters of AR. More importantly, LNCaP-Id4 cells were able to synthesize significantly higher levels of testosterone as compared to the androgen-dependent LNCaP cells. In conclusion, we demonstrate that loss of Id4 in LNCaP cells elevates FKBP52 levels, transcriptionally potentiates AR activity which in turn then leads to progression of androgen-independent prostate cancer. NIH grant #R01CA128914 Citation Format: Jugal B. Joshi. Id4 and FKBP52 interaction regulates androgen receptor activity in normal prostate and prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3253. doi:10.1158/1538-7445.AM2014-3253