2. Academic Validation
  3. Chronic hypoxia stabilizes 3βHSD1 via autophagy suppression

Chronic hypoxia stabilizes 3βHSD1 via autophagy suppression

  • Cell Rep. 2023 Dec 13:113575. doi: 10.1016/j.celrep.2023.113575.
Liang Qin 1,  Michael Berk 2,  Yoon-Mi Chung 3,  Di Cui 4,  Ziqi Zhu 3,  Abhishek A Chakraborty 2,  Nima Sharifi 5
Affiliations

Affiliations

  • 1 Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 2 Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 3 Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • 4 Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • 5 Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: nimasharifi@miami.edu.
PMID: 38181788 DOI: 10.1016/j.celrep.2023.113575
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. 3β-Hydroxysteroid dehydrogenase/Δ5-->4 isomerase 1 (3βHSD1) catalyzes the rate-limiting step in androgen synthesis. However, how 3βHSD1, especially the "adrenal-permissive" 3βHSD1(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 3βHSD1(367T) protein levels. Our results show that, in vitro, hypoxia stabilizes 3βHSD1 protein by suppressing Autophagy. Autophagy inhibition promotes 3βHSD1-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.

Keywords

3βHSD1; CP: Cancer; CP: Molecular biology; androgen synthesis; autophagy; enzyme; germline; hypoxia; metabolism; prostate cancer; protein; steroid.

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