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The CCAAT Enhancer-Binding Protein- Negatively Regulates the Transactivation of Androgen Receptor in Prostate Cancer Cells

Hormone Research Center (S.C., E.-Y.G., M.H., E.P., H.J.L., C.Y., H.-S.C., H.B.K., K.L.) School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea; and Department of Molecular Biology (J.-H.C.), College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea

Address all correspondence and requests for reprints to: Keesook Lee, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea. E-mail: klee{at}chonnam.ac.kr.

The basic leucine zipper transcription factor, CCAAT enhancer-binding protein- (C/EBP), negatively regulates cell proliferation and induces terminal differentiation of various cell types. C/EBP is expressed in the prostate, but its potential role in the tissue is unknown. Herein, we show that C/EBP is highly expressed at the stage of growth arrest during prostate development. Furthermore, overexpression of C/EBP decreases the rate of DNA synthesis in LNCaP prostate cancer cells. Investigation of the potential cross-talk between C/EBP and androgen receptor (AR) that is responsible for androgen-dependent prostate proliferation demonstrates that androgen-dependent transactivation of AR is strongly repressed by C/EBP. C/EBP directly binds AR in vitro and forms a complex with AR in vivo. C/EBP 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/EBP does compete with AR coactivators for AR binding. Additionally, C/EBP 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/EBP as a potent AR corepressor and provide insight into the role of C/EBP in prostate development and cancer.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   p300  |  SRC-1  |  GRIP1  |  ARA70

Ligands:   Dihydrotestosterone

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