Abstract
The activated androgen receptor (AR) promotes prostate cancer (PCa) growth. AR antagonists repress the AR by recruitment of corepressors. Not much is known about the inactivation of AR by corepressors in the presence of agonists (androgens). Here we show that the corepressor LCoR acts as an androgen-dependent corepressor that represses human PCa growth in vivo. In line with this, progressive decrease of ligand-dependent corepressor expression was observed in the PCa TRAMP mouse model with increasing age. LCoR interacts with AR and is recruited to chromatin in an androgen-induced manner. Unexpectedly, the LXXLL motif of LCoR is dispensable for interaction with the AR. Rather, the data indicate that LCoR interacts with the AR DNA binding domain on DNA. Interestingly, the interaction of LCoR with AR is inhibited by signaling pathways that are associated with androgen-independent PCa. Here we also show that the Src kinase inactivates the corepressive function of LCoR. Interfering with endogenous Src function by a dominant negative Src mutant, the growth inhibitory activity of LCoR is enhanced in vivo in a xenograft mouse model system. Thus, our studies indicate a role of LCoR as an AR corepressor and a tumor suppressor. Further, the decreased expression or inactivation of LCoR is as an important step toward PCa carcinogenesis in vivo.
Background: Prostate cancer (PCa) growth is promoted by the androgen receptor (AR). Castration-resistant PCa is associated with activated signaling pathways.
Results: LCoR represses human PCa growth in vivo. Src kinase inactivates the corepressive function of LCoR in vivo.
Conclusion: LCoR, a novel corepressor for AR, inhibits PCa cell growth in vivo. LCoR is inactivated by Src kinase in castration-resistant PCa.
Significance: As a ligand-dependent CoR, LCoR is able to inhibit AR activity in the presence of agonists in comparison to SMRT, Alien, or NCoR and thus could offer new therapies without applying antagonists, which result in androgen-independent growth. For this, the target could be the here-described Src pathway.