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

Abstract

Nuclear expression of CCAAT enhancer binding protein-α (C/EBPα), which supports tissue differentiation through several antiproliferative protein–protein interactions, augurs terminal differentiation of prostate epithelial cells. C/EBPα is also a tumor suppressor, but in many tumors its antiproliferative interactions may be attenuated by de-phosphorylation. C/EBPα 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/EPBα recruits AR to activate transcription. C/EBPα-dependent trans-activation by AR also overrode suppression of AREs by C/EBPα 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/EBPα. This unique mechanism explains the functional coordination between AR and C/EPBα in the prostate and also shows that hormone-refractory AR signaling in prostate cancer could occur through receptor tethering.

Androgen receptor activation integrates complex transcriptional effects in osteoblasts, involving the growth factors TGF-β and IGF-I, and transcription factor C/EBPδ

“…In prostate cancer cells, C/EBPα interacts with hormone activated AR and prevents gene expression through AR REs (Chattopadhyay et al, 2006;Zhang et al, 2010), consistent with the inhibitory effect of C/EBPδ on AR dependent gene expression that can occur in osteoblasts. C/EBPδ also drives the expression of the steroid metabolizing enzyme 3-ketoreductase which can convert androgenic substrates to activating ligands for ERα in osteoblasts, and thereby also reduce the levels of functional AR ligands.…”

The ETS Domain Transcription Factor ELK1 Directs a Critical Component of Growth Signaling by the Androgen Receptor in Prostate Cancer Cells

“…activation of the PSA gene) was reflected by the absent or poor sensitivity of the former to Casodex. We have previously demonstrated that tethered association of AR with its target sites could be hormone-independent when the cells are independent of hormone for nuclear import of AR (21). The recruitment of AR by ELK1 represents the first example in which an AR-tethering protein binds to the N-terminal A/B domain of AR.…”

“…The pattern of expression of AR-tethering proteins during development, differentiation, and malignant transformation of the prostate could redirect AR signaling according to the physiological context. This may be exemplified by the established AR-tethering proteins, including HoxB13 (involved in development) (50) and CCAAT/enhancer-binding protein ␣ (involved in terminal differentiation) (21,51) as well as ELK1 (demonstrated in this study to be required for growth).…”

“…Furthermore, we have demonstrated that in those cells the AR apoprotein can support growth through gene activation that occurs without the direct binding of AR to AREs and likely through tethered associations of the receptor with its target genes (9). Our previous detailed studies of the interaction of AR with CCAAT/enhancer-binding protein ␣ (involved in terminal tissue differentiation) suggested that tethered associations of AR with DNA may not require hormone except in cell contexts in which androgen is needed for nuclear import of AR (21). Therefore, it may be possible to identify one or a few critical AR-tethering proteins whose interaction with the receptor may be necessary, although not sufficient, for androgen/AR-dependent growth of both early stage and advanced prostate cancer cells.…”

The Amino-terminal Domain of the Androgen Receptor Co-opts Extracellular Signal-regulated Kinase (ERK) Docking Sites in ELK1 Protein to Induce Sustained Gene Activation That Supports Prostate Cancer Cell Growth

“…Among the known DNA-binding proteins that have been suggested to recruit AR, the interactions of AR with HoxB13 and C/EBPa are perhaps the best studied. HoxB13 interacts with the DNA binding domain of AR (29), whereas C/EBPa did not show a strong AR domain selectivity for interaction, and its association with AR involved multiple AR domains (30). Relatively little is known about the structural basis for non-genomic interactions of AR and other nuclear receptors with signaling pathways involving MAPK, PI3K/Akt, PKC, PLC, and G-protein-coupled receptors (1).…”