Figure 4.

Forms of epigenetic and chromatin dysregulation in PC. DNA methylation is increased at specific regulatory regions, such as the GSTP1 promoter, but is generally reduced genome-wide. Aberrant histone modifications especially at distal regulatory regions, often harboring binding motifs for key transcription factors (TFs) such as the androgen receptor (AR), shift to a more active state. This also occurs due to the action of transcriptional coactivators and chromatin readers such as BRD4, leading to recruitment of these TFs to previously repressed regions. Loss of CHD1 induces chromatin rewiring, and pioneer factors such as FOXA1 are able to bind to repressed regions and recruit other TFs and histone remodeling complexes. Dysregulation of chromatin accessibility is partly due to increased activity of the SWI/SNF remodeling complex, which shifts the chromatin towards more permissive states, a process termed chromatin relaxation. Figure created with BioRender.com.