Coregulators determine androgen receptor activity in prostate cancer.

The androgen receptor (AR) is the main driver of nearly all prostate cancer (PCa). It alters gene expression by binding to specific cis-regulatory elements on the DNA. Where the AR binds in the genome determines what genes are expressed. However, the AR cistrome is not static and dramatically changes during PCa initiation and progression to activate distinct transcriptional programs that fuel disease growth and therapeutic resistance. Emerging evidence suggests that these changes in DNA binding are not caused by chromatin accessibility but rather from interactions with AR coregulators. These proteins influence AR at every step of its activity and play a critical role in DNA binding and gene activation. These context-specific coregulator interactions can stabilize AR binding with DNA that has low- to moderate-affinity and also affect locus-specific epigenetic modifications to promote transcription. Given their critical role in this process, alterations to coregulator proteins define the normal and oncogenic cistrome and profoundly affect AR-mediated gene transcription. In this review, we aim to provide a new perspective on the role of AR coregulators in transcriptional activity, how these interactions evolve through different stages of PCa and their potential as therapeutic targets in advanced disease.