MECOM Function Is Critical for AR-Driven Treatment-Resistant Prostate Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Prostate cancer progression involves androgen receptor (AR) cistrome reprogramming.
• Castrate-resistant prostate cancer (CRPC) often utilizes non-canonical AR signaling resistant to AR signaling inhibitors (ARSI).

Purpose of the Study:

• To identify factors involved in non-canonical AR signaling in CRPC.
• To investigate the role of MECOM/EVI1 in prostate cancer.
• To explore MECOM/EVI1 as a predictive biomarker for PARP inhibitor therapy.

Main Methods:

• Identified EVI1 as an AR-recruited co-activator.
• Analyzed MECOM expression in CRPC and enzalutamide-resistant CRPC.
• Depleted MECOM in prostate cancer cells to assess effects on proliferation, survival, and super-enhancers (SEs).
• Assessed the susceptibility of MECOM-overexpressing cells to PARP inhibitors.

Main Results:

• MECOM was exclusively overexpressed in CRPC and enzalutamide-resistant CRPC, interacting with AR.
• MECOM depletion reduced proliferation, altered survival pathways, decreased SEs, and increased apoptosis.
• Cells overexpressing MECOM/EVI1 showed sensitivity to PARP inhibitors, irrespective of DNA damage response or HRR gene mutation status.

Conclusions:

• EVI1 plays a critical role in cell survival within the AR-reprogrammed chromatin landscape of prostate cancer.
• MECOM overexpression is a potential biomarker for broadening PARP inhibitor use beyond HRR-mutated cancers.