Research Papers:
PC-1 works in conjunction with E3 ligase CHIP to regulate androgen receptor stability and activity
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Abstract
Jian Wang1,*, Hui Zhang2,*, Xiaoqing Zhang1, Peng Wang1, Hongtao Wang1, Fang Huang1, Chenyan Zhou1, Jianguang Zhou1, Shanhu Li1
1Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China
2School of Medicine, Tsinghua University, Beijing 100084, China
*These authors contributed equally to this work
Correspondence to:
Shanhu Li, email: [email protected]
Jianguang Zhou, email: [email protected]
Keywords: androgen receptor, prostate cancer, PC-1, CHIP, protein degradation
Received: February 10, 2016 Accepted: November 01, 2016 Published: November 09, 2016
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.
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