New Mechanisms of Androgen Receptor Signaling

by Zhang, Juan

The classical mechanism of gene activation by androgen entails ligand-induced dimerization of the androgen receptor (AR) for avid binding to repeat half-sites of a target androgen response element (ARE). It is commonly assumed that the critical hormone-independent transcriptional signaling by AR that supports the growth of many prostate tumors also occurs through the ARE. However, our studies revealed that in the prostate cancer cells in which proliferation was predominantly supported by AR but was independent of hormone, the expression of 1291 genes was directly or indirectly supported by AR, independent of hormone and significantly overlapping gene subsets most consistently up-regulated in hormone refractory clinical tumors, when the cells also retained an androgen responsive gene expression profile. Furthermore, functional and physical association of AR with the ARE requires androgen. Hormone-independent AR recruitment sites in the chromatin identified using tiling arrays lacked enrichment in AREs. The results suggest that non-classical/tethering mechanisms of target gene associations of AR rather than binding to ARE can be hormone-independent and are critical for androgen-independence in prostate cancer cells. In the following studies, we demonstrated that CCAAT/enhancer binding protein ? (C/EPB?), which is extensively expressed in the normal prostate with special temporal and sub-cellular localization pattern and also in malignant prostate tumors where its relative levels correlate significantly with those of AR, especially in metastatic tumors, can recruit AR to activate genes through its consensus sequence. This mechanism was also 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 promoter associations in situ supported the direct bimodal regulation of AR transcriptional signaling by C/EBP?. The mechanism allows for functional coordination between these two important proteins in the androgen-induced development of the prostate; it also suggests a permissive role for C/EBP? in hormone-refractory AR signaling in prostate tumors in which C/EBP?'s antiproliferative functions may be attenuated.