Targeting of steroidogenic enzymes (e.g. abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors. Pharmacological inhibition of LRH-1 activity attenuated LRH-1-mediated androgen deprivation and antiandrogen resistance of prostate cancer cells. Our findings not only demonstrate the significant role of LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management.
Cancer research. 2018 Feb 08 [Epub ahead of print]
Lijia Xiao, Yuliang Wang, Kexin Xu, Hao Hu, Zhenyu Xu, Dinglan Wu, Zhu Wang, Wenxing You, Chi-Fai Ng, Shan Yu, Franky Leung Chan
School of Biomedical Sciences, Chinese University of Hong Kong., Department of Urology, Peking University People's Hospital., Surgery, Chinese University of Hong Kong., School of Biomedical Sciences, Chinese University of Hong Kong .