HSD3B1 Positively Regulated by Androgen Receptor Signaling in Prostate Cancer

The HSD3B1 gene is positively regulated by androgens and androgen receptors (ARs), a finding that may play a role in more tailored treatment of prostate cancer, according to a study recently published in Endocrinology.

Researchers led by Nima Sharifi, MD, of the Cleveland Clinic in Cleveland, Ohio, point out that prostate cancer requires gonadal testosterone (T) for growth and progression, and advanced prostate cancer initially responds to androgen deprivation therapy (ADT; castration) but cancer treated by this castration results in castration-resistant prostate cancer.

The androgen-synthesizing enzyme 3βHSD1, encoded by HSD3B1, converts dehydroepiandrosterone (DHEA) to androstenedione (AD), and regulates the rate limiting step in the conversion of DHEA to the potent androgens T and dihydrotestosterone (DHT). “A genetic variant of HSD3B1—1245A>C; rs1047303—results in decreased proteasomal degradation of 3βHSD1 and in a strikingly dimorphic shift in DHEA metabolism, likely leading to increased DHT synthesis from extragonadal precursor steroids in metastatic tumors,” the authors write. They go on to write that their previous studies have shown that patients who inherit this HSD3B1 variant have worse outcomes when undergoing ADT. “This is mechanistically attributable to the ability of tumors harboring the variant to more effectively use adrenal DHEA/DHEA sulfate for tumor androgen synthesis to fuel tumor growth when gonadal T is no longer available because of ADT,” they write.

The researchers wanted to find out how the transcriptional regulation of HSD3B1 works in prostate cancer, since relatively little is known about this process. “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,” the authors write.

Using cell cultures and mice, the researchers 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. “We found that in multiple CRPC models, HSD3B1 is induced by the synthetic androgen R1881 and that this effect can be abrogated by the AR antagonist enzalutamide,” the authors write. “3βHSD1 protein is also induced, and enzyme functionality was confirmed by measuring flux from DHEA to AD and other downstream metabolites via HPLC. Further, HSD3B1 mRNA and protein are suppressed in an in vivo VCaP xenograft model after castration.”

The authors note that they were surprised by these results, and had actually anticipated the opposite, since T deprivation spurs an increase in compensatory androgen synthesis. “Namely,” the authors write, “we fully expected that AR stimulation would instead suppress HSD3B1 transcript and potent androgen synthesis from extragonadal precursor steroids.” Still, based on these results, the researchers conclude that HSD3B1 is unexpectedly positively regulated by androgens and ARs. They go on to write that there are potential clinical implications, such as the use of enzalutamide, a direct AR antagonist, and testing for HSD3B1(1245C) germline variant inheritance.

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