An Integrated Cell-Death Program Defines Aggressive Prostate Cancer by Coupling Ezrin to the Hippo-YAP/TAZ Axis

Area of Science:

• Oncology
• Molecular Biology
• Biomarker Discovery

Background:

• Prostate cancer (PCa) has heterogeneous outcomes, necessitating biomarkers reflecting tumor biology.
• Programmed cell death (PCD) is crucial for tumor suppression, but its prognostic role in PCa is unclear.

Purpose of the Study:

• To develop and validate a prognostic model for prostate cancer based on programmed cell death pathways.
• To investigate the relationship between PCD activity, tumor microenvironment, and therapeutic response in PCa.

Main Methods:

• Constructed 14 PCD prognostic models, integrating top three (apoptosis, entosis, necroptosis) into an AEN score.
• Validated the AEN score in independent PCa cohorts, analyzing tumor microenvironment, drug sensitivity, and single-cell data.
• Performed Mendelian randomization and functional assays to identify causal drivers.

Main Results:

• The AEN score demonstrated strong predictive performance (AUC=0.857) and independently predicted biochemical recurrence (HR=8.02).
• High-AEN tumors showed non-inflamed TME, predicted immunotherapy resistance, and increased chemosensitivity.
• EZR was identified as a causal driver, with its knockdown suppressing proliferation and tumor growth via YAP/TAZ dysregulation.

Conclusions:

• The AEN score serves as a robust prognostic tool, linking PCD activity to PCa aggressiveness and immune evasion.
• EZR is identified as a functional effector and potential therapeutic target in PCa, acting through Hippo signaling.