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The Role of Hepatocyte Nuclear Factor-3 (Forkhead Box A1) and Androgen Receptor in Transcriptional Regulation of Prostatic Genes

Department of Cell and Developmental Biology (N.G., J.Z., R.J.M.), Vanderbilt University Medical Center; Department of Urologic Surgery (N.G., J.Z., T.C.C., J.M., Y.W., R.J., A.G., R.J.M.), and the Vanderbilt Prostate Cancer Center, Vanderbilt University; Department of Cancer Biology (T.C.C., J.M., Y.W., R.J., A.G., R.J.M.), and the Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232; and The Prostate Centre at Vancouver General Hospital (M.A.R., P.S.R.), Vancouver, British Columbia V6H 3Z6, Canada

Address all correspondence and requests for reprints to: Robert J. Matusik, Ph.D., Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232. E-mail: Robert.matusik{at}vanderbilt.edu.

Androgens and mesenchymal factors are essential extracellular signals for the development as well as the functional activity of the prostate epithelium. Little is known of the intraepithelial determinants that are involved in prostatic differentiation. Here we found that hepatocyte nuclear factor-3 (HNF-3), an endoderm developmental factor, is essential for androgen receptor (AR)-mediated prostatic gene activation. Two HNF-3 cis-regulatory elements were identified in the rat probasin (PB) gene promoter, each immediately adjacent to an androgen response element. Remarkably, similar organization of HNF-3 and AR binding sites was observed in the prostate-specific antigen (PSA) gene core enhancer, suggesting a common functional mechanism. Mutations that disrupt these HNF-3 motifs significantly abolished the maximal androgen induction of PB and PSA activities. Overexpressing a mutant HNF-3 deleted in the C-terminal region inhibited the androgen-induced promoter activity in LNCaP cells where endogenous HNF-3 is expressed. Chromatin immunoprecipitation revealed in vivo that the occupancy of HNF-3 on PSA enhancer can occur in an androgen-depleted condition, and before the recruitment of ligand-bound AR. A physical interaction of HNF-3 and AR was detected through immunoprecipitation and confirmed by glutathione-S-transferase pull-down. This interaction is directly mediated through the DNA-binding domain/hinge region of AR and the forkhead domain of HNF-3. In addition, strong HNF-3 expression, but not HNF-3ß or HNF-3, is detected in both human and mouse prostatic epithelial cells where markers (PSA and PB) of differentiation are expressed. Taken together, these data support a model in which regulatory cues from the cell lineage and the extracellular environment coordinately establish the prostatic differentiated response.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Ligands:   Dihydrotestosterone  |  R1881

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