Chronic hypoxia stabilizes 3βHSD1 via autophagy suppression

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Prostate cancer progression relies on androgen receptor signaling, typically targeted by androgen deprivation therapy.
• Resistance develops into castration-resistant prostate cancer (CRPC), driven by tumor-synthesized androgens.
• 3β-Hydroxysteroid dehydrogenase/Δ5-->4 isomerase 1 (3βHSD1) is crucial for androgen synthesis, but its protein-level regulation, especially under hypoxia, is unclear.

Purpose of the Study:

• To investigate the regulatory mechanisms of 3βHSD1 protein levels by hypoxia.
• To understand the role of autophagy and histone acetylation in hypoxia-induced 3βHSD1 regulation.
• To explore potential therapeutic targets for CRPC.

Main Methods:

• In vitro experiments to assess 3βHSD1 protein stability under hypoxic conditions.
• Analysis of autophagy activity and its relationship with 3βHSD1 levels.
• Investigation of histone acetylation and autophagy-related (ATG) gene expression.
• Evaluation of histone deacetylase (HDAC) inhibition effects.

Main Results:

• Hypoxia was found to stabilize 3βHSD1 protein by suppressing autophagy in vitro.
• Autophagy inhibition was linked to increased 3βHSD1-dependent tumor progression.
• Hypoxia represses ATG gene transcription via decreased histone acetylation.
• HDAC inhibition restored ATG gene transcription under hypoxic conditions.

Conclusions:

• Hypoxia stabilizes 3βHSD1 protein by inhibiting autophagy, thereby promoting CRPC progression.
• HDAC inhibition represents a potential therapeutic strategy to counteract hypoxia-driven androgen synthesis in prostate cancer.