Genome-wide CRISPR screens identify PTGES3 as a novel AR modulator

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen receptor (AR) is a critical driver of prostate cancer (PCa).
• Understanding regulators of AR protein levels and activity is crucial for developing new therapies.
• Existing therapies targeting AR can lead to resistance.

Purpose of the Study:

• To systematically identify genes that modulate AR protein levels and oncogenic activity.
• To investigate the role of PTGES3 as a potential therapeutic target in PCa.
• To explore PTGES3's mechanism of action in regulating AR function.

Main Methods:

• Development of live cell quantitative endogenous AR fluorescent reporters.
• Genome-scale CRISPRi flow cytometry sorting screens to identify AR modulators.
• Validation of identified genes, including PTGES3, in AR-driven PCa models.
• In vitro and in vivo studies to elucidate PTGES3's mechanism of action.

Main Results:

• Identified and validated known AR regulators (HOXB13, GATA2) and novel hits like PTGES3.
• PTGES3 repression led to AR protein loss, cell cycle arrest, and cell death in PCa models.
• PTGES3 expression is associated with resistance to AR-directed therapies.
• PTGES3 directly binds to AR, regulates its stability, and modulates its nuclear function.

Conclusions:

• PTGES3 is a novel and essential therapeutic target for prostate cancer.
• Targeting PTGES3 may overcome resistance mechanisms to existing AR-directed therapies.
• PTGES3 plays a significant role in AR protein regulation and oncogenic activity in PCa.