The expression of glucocorticoid receptor is negatively regulated by active androgen receptor signaling in prostate tumors

The glucocorticoid and androgen receptors (GR and AR) can commonly regulate up to 50% of their target genes in prostate cancer (PCa) cells. GR expression is stimulated by castration therapy, which has been proposed to be one mechanism that compensates for AR signaling blockade and promotes castration-resistant PCa (CRPC) progression. However, whether GR functions as a driver for CRPC or a marker reflecting AR activity remains unclear. Here, we applied PCa tissue microarrays to show that GR protein levels were elevated by castration therapy, but reduced to pre-castration levels when tumors were at the CRPC stage. Using subrenal capsule xenograft models, we showed that GR expression was inversely correlated with AR and PSA expressions. GR expression levels are not associated with tumor invasion and metastasis phenotypes. In castration-resistant C4-2 xenografts expressing AR shRNA, regressing tumors induced by AR knockdown expressed higher levels of GR and lower levels of PSA than non-regressing tumors. Immunoblotting and real-time PCR assays further showed that AR knockdown or AR antagonists increased GR expression at both mRNA and protein levels. ChIP combined with DNA sequencing techniques identified a negative androgen responsive element (nARE) 160K base pairs upstream of the GR gene. Gel shift assays confirmed that AR directly interacted with the nARE and luciferase assays demonstrated that the nARE could mediate transcription repression by ligand-activated AR. In conclusion, GR expression is negatively regulated by AR signaling and may serve as a marker for AR signaling in prostate tumors.