Hypoxia-Reoxygenation Couples 3βHSD1 Enzyme and Cofactor Upregulation to Facilitate Androgen Biosynthesis and Hormone Therapy Resistance in Prostate Cancer

Androgen deprivation therapy suppresses tumor androgen receptor (AR) signaling by depleting circulating testosterone and is a mainstay treatment for advanced prostate cancer. Despite initial treatment response, castration-resistant prostate cancer nearly always develops and remains driven primarily by the androgen axis. Here we investigated how changes in oxygenation affect androgen synthesis. In prostate cancer cells, chronic hypoxia coupled to reoxygenation resulted in efficient metabolism of androgen precursors to produce androgens and activate AR. Hypoxia induced 3 beta HSD1, the rate-limiting androgen synthesis regulator, and reoxygenation replenished necessary cofactors, suggesting that hypoxia and reoxygenation both facilitate potent androgen synthesis. The EGLN1/VHL/HIF2 alpha pathway induced 3 beta HSD1 expression through direct binding of HIF2 alpha to the 50 regulatory region of HSD3B1 to promote transcription. Over-expression of HIF2 alpha facilitated prostate cancer progression, which largely depended on 3 beta HSD1. Inhibition of HIF2 alpha with the small-molecule PT2399 prevented prostate cancer cell proliferation. These results thus identify HIF2 alpha as a regulator of androgen synthesis and potential therapeutic target in prostate cancer. Significance: Hypoxia followed by reoxygenation in prostate cancer drives androgen deprivation therapy resistance via increasing the rate-limiting enzyme and cofactors for androgen synthesis, revealing HIF2 alpha as a therapeutic target to subvert resistance.