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