Interplay of the 3D genome and epigenome in androgen-driven prostate cancer

Understanding of the therapeutic landscape for androgen-driven prostate cancer has undergone significant evolution, yet treatment resistance remains an ongoing challenge. The androgen receptor (AR) plays a central role in androgen-dependent prostate tumor growth, and therapeutic agents targeting AR represent the main treatment modality for prostate cancer. AR transcriptional activity is tightly regulated by coregulatory transcription factors and their DNA binding and activity. However, the precise interactions between AR and three-dimensional (3D) chromatin structure and its dynamic remodeling represent a critical yet underexploited therapeutic frontier. Here, we present a perspective on how the spatial architecture of the epigenome, including 3D chromatin structure and dynamics, orchestrates dysregulation of transcription factor networks that help to drive disease progression in androgen-driven prostate cancer. We argue that successful therapeutic intervention requires moving beyond linear epigenetic marks toward a three-dimensional understanding of the epigenetic landscape. Such a shift is essential to capture the complex enhancer-promoter communications and chromatin state transitions that define the disease. Drawing on recent advances in prostate cancer biology and technological developments, we propose a unique integrated framework centered on patient-specific 3D epigenomic vulnerabilities for next-generation epigenetic therapies designed to disrupt oncogenic transcriptional programs by specifically targeting chromatin topology.