CDC25A functions as a novel Ar corepressor in prostate cancer cells.
Androgen receptor (AR) is a ligand-dependent transcription factor and its activity is regulated by numerous AR coregulators. Aberrant expression of AR coregulators in prostate cancer cells has an important role in the development and progression of prostate cancer. We report here that CDC25A, a cell cycle-promoting phosphatase over-expressed in a number of cancers, functions as an AR coregulator suppressing the AR transcriptional activity. In this study, we found that CDC25A is upregulated in human prostate cancer and its expression level is positively associated with the Gleason score and disease metastasis. More importantly, we showed that CDC25A can physically interact with AR through its putative catalytic domain. In addition, ectopic expression of CDC25A in prostate cancer cell lines suppresses PSA and Probasin promoter activities significantly, indicating that CDC25A may function as an AR corepressor. This was further confirmed by knockdown of endogenous CDC25A expression using small interfering RNA (siRNA), which resulted in upregulation of PSA promoter activity. Moreover, a truncated mutant that does not interact with AR fails to suppress the PSA promoter activity, indicating that CDC25A downregulates androgen-responsive promoter by physically interacting with AR. Taken together, our results demonstrated a novel function of CDC25A in the regulation of androgen signaling in human prostate cancer cells.
Chiu
Yung-Tuen
YT
Cancer Biology Group, Department of Anatomy, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, SAR, China.
Han
Hui-Ying
HY
Leung
Steve Chin-Lung
SC
Yuen
Hiu-Fung
HF
Chau
Chee-Wai
CW
Guo
Zhiyong
Z
Qiu
Yun
Y
Chan
Kwok-Wah
KW
Wang
Xianghong
X
Wong
Yong-Chuan
YC
Ling
Ming-Tat
MT
D059002:Androgen Receptor Antagonists; D000727:Androgen-Binding Protein / Q000096:biosynthesis; D002460:Cell Line; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008297:Male; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism*
D059002:Androgen Receptor Antagonists; D000727:Androgen-Binding Protein; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C027519:probasin; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D017430:Prostate-Specific Antigen