Chronic hypoxia stabilizes 3HSD1 via autophagy suppression

Progression of prostate cancer depends on androgen receptor, which is usually activated by androgens. Therefore, a mainstay treatment is androgen deprivation therapy. Unfortunately, despite initial treatment response, resistance nearly always develops, and disease progresses to castration -resistant prostate cancer (CRPC), which remains driven by non -gonadal androgens synthesized in prostate cancer tissues. 3 beta-Hydroxysteroid dehydrogenase/A(5-->4) isomerase 1 (3 beta HSD1) catalyzes the rate -limiting step in androgen synthesis. However, how 3 beta HSD1, especially the "adrenal-permissive"3 beta HSD1(367T) that permits tumor synthesis of androgen from dehydroepiandrosterone (DHEA), is regulated at the protein level is not well understood. Here, we investigate how hypoxia regulates 3 beta HSD1(367T) protein levels. Our results show that, in vitro, hypoxia stabilizes 3 beta HSD1 protein by suppressing autophagy. Autophagy inhibition promotes 3 beta HSD1-dependent tumor progression. Hypoxia represses transcription of autophagy-related (ATG) genes by decreasing histone acetylation. Inhibiting deacetylase (HDAC) restores ATG gene transcription under hypoxia. Therefore, HDAC inhibition may be a therapeutic target for hypoxic tumor cells.