Identification and Functional Characterization of a Novel Androgen Receptor Coregulator, EAP1

Abstract

The androgen receptor (AR) plays an essential role in the development of prostate cancer and androgen deprivation therapy is used as a first-line treatment for prostate cancer. However, under androgen deprivation therapy, castration-resistant prostate cancer inevitably arises, suggesting that the interacting transcriptional coregulators of AR are promising targets for developing novel therapeutics. In this study, we utilized novel proteomic techniques to evaluate the AR interactome, including biochemically labile binding proteins, which might go undetected by conventional purification methods. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, we identified enhanced at puberty 1 (EAP1) as a novel AR coregulator, whereas its interaction with AR could not be detected under standard biochemical conditions. EAP1 enhanced the transcriptional activity of AR via the E3 ubiquitin ligase activity and its ubiquitination substrate proteins included AR and HDAC1. Furthermore, in prostate cancer specimens, EAP1 expression was significantly correlated with AR expression as well as a poor prognosis of prostate cancer. Together, these results suggest that EAP1 is a novel AR coregulator that promotes AR activity and potentially plays a role in prostate cancer progression.

The physiological and pathophysiological roles of carbohydrate response element binding protein in the kidney

“…For tissue-specific regulation of ChREBP activity, further analysis of the molecular mechanisms of ChREBP regulation in each tissue is required. Given that transcription factors generally form transcriptional coregulator complexes in a tissue-specific manner [64][65][66][67], it would be of interest to search for such protein complexes which ChREBP forms using a proteomic approach [67][68][69][70][71], and to determine whether these complexes could be a potential drug target for tissue-specific ChREBP activation/ inhibition.…”

Regulating Androgen Receptor Function in Prostate Cancer: Exploring the Diversity of Post-Translational Modifications

“…However, EAP1 does not directly bind AR. Further investigations into how EAP1 accomplishes this will need to be conducted to understand the mechanism [146].…”

Recent advances in prostate cancer: WNT signaling, chromatin regulation, and transcriptional coregulators

“…Rapid immunoprecipitation mass spectrometry of endogenous protein experiments 113 in LNCaP cells identified enhanced at puberty 1 (EAP1/IRF2BPL) as a coactivator for AR. 114 EAP1 enhances the transcriptional activity of AR through E3 ubiquitin ligase activity, and its ubiquitination substrates include AR and HDAC1. EAP1 is highly expressed in prostate cancer, and EAP1 knockdown reduces endogenous mRNA expression of AR target genes such as PSA and kallikrein-related peptidase 2 (KLK2).…”