1. ¹Department of Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, OH, USA
2. ²Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Trent Drive, Durham, NC, USA
3. ³Department of Biological Sciences, University of Toledo, W. Bancroft, Toledo, OH, USA
4. ⁴Bioinformatics and Proteomics/Genomics Core Division, Medical University of Ohio, Toledo, OH, USA

Correspondence: Professor M Ratnam, Department of Biochemistry and Cancer Biology, Medical University of Ohio, Block Health Science Building, 3000 Arlington Avenue, Toledo, OH 43614, USA. E-mail: manohar.ratnam@utoledo.edu

⁵These authors contributed equally to this work.

Received 23 April 2009; Revised 24 June 2009; Accepted 28 September 2009; Published online 9 November 2009.

Abstract

Nuclear expression of CCAAT enhancer binding protein- (C/EBP), which supports tissue differentiation through several antiproliferative protein–protein interactions, augurs terminal differentiation of prostate epithelial cells. C/EBP is also a tumor suppressor, but in many tumors its antiproliferative interactions may be attenuated by de-phosphorylation. C/EBP acts as a corepressor of the classical androgen response element (ARE)-mediated gene activation by the androgen receptor (AR), but this is paradoxical as the genotropic actions of AR are crucial not only for the growth of the prostate but also for its maintenance and function. We show that DNA-bound C/EPB recruits AR to activate transcription. C/EBP-dependent trans-activation by AR also overrode suppression of AREs by C/EBP elsewhere in a promoter. This mechanism was remarkable in that its androgen dependence was apparently for nuclear translocation of AR; it was otherwise androgen independent, flutamide insensitive and tolerant to disruption of AR dimerization. Gene response profiles and global chromatin associations in situ supported the direct bimodal regulation of AR transcriptional signaling by C/EBP. This unique mechanism explains the functional coordination between AR and C/EPB in the prostate and also shows that hormone-refractory AR signaling in prostate cancer could occur through receptor tethering.