Androgen receptor (AR) signaling is the central signal transduction pathway in prostate cancer. Many different epigenetic mechanisms affecting this critical pathway play a role in disease initiation and progression. This includes the presence of AR variants that are constitutively transcriptionally active, interference with histone demethylase coactivators, and the formation of gene fusions of AR-responsive genes with transcription factors like ERG.
Androgen Receptor (AR) transcripts can include cryptic exons, which result in early termination of translation and proteins lacking in the ligand binding domain. AR-V7, a variant arising from a cryptic exon, leads to aberrant transcriptional regulation and is frequently expressed in castration-resistant prostate cancer (CRPC).
In some prostate cancers, Glucocorticoid Receptor (GR) signaling may aberrantly override expression of AR targets, inducing further cancer progression and AR-treatment resistance. In these instances, inhibition of Ezh2, which can act as a coactivator for Androgen Receptor, offers additional treatment options.
HOXB13 is a transcription factor and marker of prostate cancer that is used to identify metastasis.
ERG overexpression occurs due to gene fusion with the androgen-driven promoter of the TMPRSS2 gene and is a key driver of prostate cancer metastasis.
