Chronic hypoxia stabilizes 3βHSD1 via autophagy suppression

• DOI: 10.1016/j.celrep.2023.113575
• Publication Date: 2024-01-04T15:38:04Z
• Authors: Liang Qin; Michael Berk; Yoon-Mi Chung; Di Cui; Ziqi Zhu; Abhishek A. Chakr...; Nima Sharifi
• Keywords: Hypoxia

Progression of prostate cancer depends on androgen receptor, which is usually activated by androgens. Therefore, a mainstay treatment deprivation therapy. Unfortunately, despite initial response, resistance nearly always develops, and disease progresses to castration-resistant (CRPC), remains driven non-gonadal androgens synthesized in tissues. 3β-Hydroxysteroid dehydrogenase/Δ5-->4 isomerase 1 (3βHSD1) catalyzes the rate-limiting step synthesis. However, how 3βHSD1, especially "adrenal-permissive" 3βHSD1(367T) that permits tumor synthesis from dehydroepiandrosterone (DHEA), regulated at protein level not well understood. Here, we investigate hypoxia regulates levels. Our results show that, vitro, stabilizes 3βHSD1 suppressing autophagy. Autophagy inhibition promotes 3βHSD1-dependent progression. Hypoxia represses transcription autophagy-related (ATG) genes decreasing histone acetylation. Inhibiting deacetylase (HDAC) restores ATG gene under hypoxia. HDAC may be therapeutic target for hypoxic cells.