Androgen receptor acts as the transcriptional repressor of the nuclear receptor LRH-1 via the androgen-driven chromatin looping conformation in prostate cancer

The androgen receptor (AR) signaling axis is regarded as the key driver of prostate cancer (PCa). Besides acting as a well-characterized transactivator of diverse targets, accumulating evidence suggests that AR can also function as a transrepressor. However, AR-repressed targets and their significance in PCa and castration-resistant PCa (CRPC) remain poorly understood. Among multiple mechanisms, intratumoral androgen biosynthesis is regarded as an important factor responsible for persistent AR signaling in CRPC. Previously, we characterized that the nuclear receptor LRH-1 (NR5A2) plays a key role in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of multiple key steroidogenic enzymes. However, the transcriptional control of LRH-1 in PCa is still undefined. In this study, we show that androgen-activated AR could suppress, whereas antiandrogen-suppressed AR could up-regulate the LRH-1 expression in PCa cells. Furthermore, our genomics analysis showed that the transcriptional repression of NR5A2 by ligand-activated AR was mediated through the induction of a distinct androgen-dependent chromatin looping formed within the topologically associated domain of NR5A2 via direct binding of AR to the regulatory elements of NR5A2. Our present study demonstrates the significance of decreased androgen levels in androgen-deprivation therapy, resulting in the relief or up-regulation of LRH-1 toward intratumoral androgen biosynthesis in CRPC.