Abstract 122: Hypoxia-reoxygenation couples enzyme and cofactor upregulation to quicken prostate cancer androgen biosynthesis and hormone therapy resistance

Abstract

Abstract Androgen deprivation therapy depletes circulating testosterone and is the mainstay treatment for advanced prostate cancer by suppressing tumor androgen receptor signaling. Despite initial treatment response, castration-resistant prostate cancer nearly always develops and remains driven primarily by the androgen axis. We investigated how changes in oxygenation affect androgen synthesis. Our study indicates that when chronic hypoxia is coupled to reoxygenation, prostate cancer cells efficiently metabolize androgen precursors to produce androgens and activate AR. Hypoxia induces 3βHSD1, the rate-limiting androgen synthesis regulator, and reoxygenation replenishes necessary cofactors. Therefore, hypoxia and reoxygenation are both essential for potent androgen synthesis. The EGLN1/VHL/HIF2α pathway promoted transcription of HSD3B1 by directly binding the 5’ regulatory region of HSD3B1. HIF2α overexpression facilitated prostate cancer progression, which largely depends on 3βHSD1. PT2399, a specific HIF2α inhibitor, prevented prostate cancer cell proliferation. Our study indicates HIF2α is a potential therapeutic target in prostate cancer. Citation Format: Liang Qin, Yoon-Mi Chung, Michael Berk, Bryan Naelitz, Eric Klein, Abhishek A Chakraborty, Nima Sharifi. Hypoxia-reoxygenation couples enzyme and cofactor upregulation to quicken prostate cancer androgen biosynthesis and hormone therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 122.