Chronic hypoxia stabilizes 3ßHSD1 via autophagy suppression.

ABSTRACT

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. 3ß-Hydroxysteroid dehydrogenase/Δ5-->4 isomerase 1 (3ßHSD1) catalyzes the rate-limiting step in androgen synthesis. However, how 3ßHSD1, especially the "adrenal-permissive" 3ßHSD1(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 3ßHSD1(367T) protein levels. Our results show that, in vitro, hypoxia stabilizes 3ßHSD1 protein by suppressing autophagy. Autophagy inhibition promotes 3ßHSD1-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.