AR Signaling in Prostate Cancer Regulates a Feed-Forward Mechanism of Androgen Synthesis by Way of HSD3B1 Upregulation

• DOI: 10.1210/en.2018-00283
• Publication Date: 2018-05-29T14:21:20Z
• Authors: Daniel Hettel; Ao Zhang; Mohammad Alyamani; Michael Berk; Nima Sharifi
• Keywords: Enzalutamide

3βHSD1 enzymatic activity is essential for synthesis of potent androgens from adrenal precursor steroids in prostate cancer. A germline variant HSD3B1, the gene that encodes 3βHSD1, a stable enzyme, regulates androgen dependence, and predictive biomarker poor clinical outcomes after gonadal testosterone deprivation therapy. However, little known about HSD3B1 transcriptional regulation. Generally, it thought intratumoral upregulated deprivation, enabling development castration-resistant Given its critical role extragonadal synthesis, we sought to directly interrogate regulation multiple metastatic cancer cell models. Surprisingly, found VCaP, CWR22Rv1, LNCaP, LAPC4 models demonstrate induction upon stimulation approximately 72 hours, followed by attenuation around 120 hours. protein levels mirrored changes harboring (LNCaP) wild-type (LAPC4) these abrogated via enzalutamide treatment. Androgen treatment increased flux [3H]-dehydroepiandrosterone androstenedione other downstream metabolites. expression was reduced hours castration VCaP xenograft mouse model, suggesting receptor (AR) also occurs vivo. Overall, data suggest unexpectedly positively regulated ARs. These may have implications strategies tailored genotype status.