PC-1 works in conjunction with E3 ligase CHIP to regulate androgen receptor stability and activity.
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.
Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
Jian
J
Wang
School of Medicine, Tsinghua University, Beijing 100084, China.
Hui
H
Zhang
Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
Xiaoqing
X
Zhang
Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
Peng
P
Wang
Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
Hongtao
H
Wang
Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
Fang
F
Huang
Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
Chenyan
C
Zhou
Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
Jianguang
J
Zhou
Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
Shanhu
S
Li
D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D055550:Protein Stability; D059748:Proteolysis; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
C410798:AR protein, human; D011944:Receptors, Androgen; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases
CHIP; PC-1; androgen receptor; prostate cancer; protein degradation