C/EBPα redirects androgen receptor signaling through a unique bimodal interaction

Nuclear expression of CCAAT enhancer binding protein-alpha (C/EBP alpha), which supports tissue differentiation through several antiproliferative protein-protein interactions, augurs terminal differentiation of prostate epithelial cells. C/EBP alpha is also a tumor suppressor, but in many tumors its antiproliferative interactions may be attenuated by de-phosphorylation. C/EBP alpha 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 alpha recruits AR to activate transcription. C/EBP alpha-dependent trans-activation by AR also overrode suppression of AREs by C/EBP alpha 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 alpha. This unique mechanism explains the functional coordination between AR and C/EPB alpha in the prostate and also shows that hormone-refractory AR signaling in prostate cancer could occur through receptor tethering. Oncogene (2010) 29, 723-738; doi: 10.1038/onc.2009.373; published online 9 November 2009