PC-1 works in conjunction with E3 ligase CHIP to regulate androgen receptor stability and activity

Jian Wang,Hui Zhang,Peng Wang,Fang Huang,Shanhu Li,Jianguang Zhou,Chenyan Zhou,Xiaoqing Zhang,Hongtao Wang

doi:10.18632/oncotarget.13230

Abstract

The androgen receptor (AR) is not only a ligand-dependent transcription factor, but also functions as a licensing factor, a component of DNA replication, which is degraded during mitosis. Furthermore, the deregulation of AR activity is involved in the initiation of prostate cancer and contributes to castration resistant prostate cancer (CRPC). While AR degradation is known to occur primarily through a proteasome-mediated pathway, very little is known about how this process is regulated, especially in M phase. PC-1 is an androgen-responsive factor and expresses specificity in prostate cancer, with higher expression noted at G2/M. In this study, PC-1 was shown to interact with AR and E3 ligase CHIP (Carboxy-terminus of Hsc70 Interacting Protein) and to enhance AR/CHIP interactions, thereby decreasing AR stability. Moreover, PC-1 was found to act in conjunction with CHIP in the decreasing of AR via ubiquitination, with the subsequent degradation predominantly occurring during M phase. PC-1 was also found to repress AR transcriptional activity in androgen-dependent and androgen-independent prostate cancer cells and attenuate the growth inhibition of AR. In conclusion, these findings should provide new clues regarding the modulation of AR turnover and activity via PC-1 and reveals an essential role of PC-1 in AR signaling.

Highlights

The androgen receptor (AR) is a ligand-dependent transcription factor belonging to the steroid hormone receptor superfamily and consists of three functional domains: the N-terminal transactivation domain, the C-terminal DNAbinding domain (DBD) and the ligand-binding domain (LBD) [1, 2]
These results indicate that PC-1 may regulate AR protein level by promoting AR degradation
Deregulation of the AR signaling pathway is crucial for prostate cancer cell proliferation, tumor progression and the development of castration resistant prostate cancer (CRPC)

Summary

Introduction

The androgen receptor (AR) is a ligand-dependent transcription factor belonging to the steroid hormone receptor superfamily and consists of three functional domains: the N-terminal transactivation domain, the C-terminal DNAbinding domain (DBD) and the ligand-binding domain (LBD) [1, 2]. In addition to functioning as a transcription factor, experimental observations suggest that AR is a licensing factor for AR-positive and androgen-sensitive prostate cancer cells and associates with licensing proteins Orc, Cdc-6, Cdt-1 and Mcm2 [4,5,6]. Abnormal AR functions, such as functional activation, are increasingly recognized in prostate cancer development and progression, with large bodies of evidence indicating that AR activities and levels are precisely modulated by many cofactors at both transcriptional and posttranslational levels. It has been reported that AR is stabilized by the S26 proteasome inhibitor MG-132, suggesting that AR is targeted for degradation through this proteasome pathway. AR must be degraded during mitosis in order to allow DNA replication to reinitiate for subsequent cell cycling, with AR stabilization during mitosis inhibiting prostate cancer proliferation [5]. While AR degradation is known to occur primarily through www.impactjournals.com/oncotarget a proteasome-dependent pathway, very little is known about how this process is regulated, especially during M phase

Methods

Results

Conclusion