The CCAAT enhancer-binding protein-alpha negatively regulates the transactivation of androgen receptor in prostate cancer cells.
The basic leucine zipper transcription factor, CCAAT enhancer-binding protein-alpha (C/EBPalpha), negatively regulates cell proliferation and induces terminal differentiation of various cell types. C/EBPalpha is expressed in the prostate, but its potential role in the tissue is unknown. Herein, we show that C/EBPalpha is highly expressed at the stage of growth arrest during prostate development. Furthermore, overexpression of C/EBPalpha decreases the rate of DNA synthesis in LNCaP prostate cancer cells. Investigation of the potential cross-talk between C/EBPalpha and androgen receptor (AR) that is responsible for androgen-dependent prostate proliferation demonstrates that androgen-dependent transactivation of AR is strongly repressed by C/EBPalpha. C/EBPalpha directly binds AR in vitro and forms a complex with AR in vivo. C/EBPalpha neither prevents the nuclear translocation of AR nor disrupts the N/C-terminal interaction of AR, which are both necessary for its proper transactivation activity upon ligand binding. To modulate AR transactivation, however, C/EBPalpha does compete with AR coactivators for AR binding. Additionally, C/EBPalpha is recruited onto AR-target promoters with AR and is further able to inhibit the expression of endogenous prostate-specific antigen in prostate cancer cells. Our results suggest C/EBPalpha as a potent AR corepressor and provide insight into the role of C/EBPalpha in prostate development and cancer.
Chattopadhyay
Soma
S
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
Gong
Eun-Yeung
EY
Hwang
Miok
M
Park
Eunsook
E
Lee
Hyun Joo
HJ
Hong
Cheol Yi
CY
Choi
Hueng-Sik
HS
Cheong
Jae-Hun
JH
Kwon
Hyuk Bang
HB
Lee
Keesook
K
D059002:Androgen Receptor Antagonists; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000032:analysis / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000737:chemistry / Q000254:growth & development / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism*; D015533:Transcriptional Activation
D059002:Androgen Receptor Antagonists; D022763:CCAAT-Enhancer-Binding Protein-alpha; D011944:Receptors, Androgen; D012097:Repressor Proteins; D017430:Prostate-Specific Antigen