3D genome architecture and epigenetic regulation of lineage identity in advanced prostate cancer

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Prostate cancer (PC) progression relies on androgen receptor (AR) signaling.
• Androgen-deprivation therapy (ADT) and AR signaling inhibitors (ARSIs) treat advanced PC but lead to castration-resistant prostate cancer (CRPC).
• CRPC can involve AR signaling reactivation (CRPC-AR) or AR-independent phenotypes driven by lineage plasticity.

Purpose of the Study:

• To explore mechanisms of CRPC progression, including AR-dependent and AR-independent phenotypes.
• To investigate the role of chromatin modifications and 3D genome structure in CRPC.
• To identify context-specific therapeutic targets for CRPC.

Main Methods:

• Review of high-resolution investigations of the 3D genome.
• Analysis of chromatin architecture and transcriptional regulation.
• Examination of lineage plasticity in CRPC subtypes like neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC).

Main Results:

• Lineage plasticity drives AR-independent CRPC phenotypes, including NEPC and DNPC.
• Chromatin modifications and 3D genome alterations are crucial for controlling lineage states in CRPC.
• Interdependence exists between chromatin architecture and transcriptional regulation in CRPC progression.

Conclusions:

• High-resolution 3D genome studies reveal critical insights into CRPC mechanisms.
• Understanding the interplay between 3D genome structure and gene expression can guide the development of novel therapeutic strategies.
• Targeting chromatin and transcriptional regulation holds promise for overcoming CRPC.