Epigenetic Coregulation of Androgen Receptor Signaling

The androgen receptor (AR) is a ligand-activated transcription factor belonging to the nuclear receptor (NR) superfamily. As with other members of the NR family, transcriptional activity of the AR is regulated by interactions with coregulatory proteins, which either enhance (coactivators) or repress (corepressors) its transcriptional activity. AR associated coregulators are functionally diverse, but a large fraction are epigenetic histone and chromatin modifiers. Epigenetic coregulators are recruited to gene regulatory regions as part of multi-protein complexes, often acting in a dynamic and inter-dependent manner to remodel chromatin, thereby allowing or inhibiting the access of AR-associated transcriptional machinery to target genes; functional consequences being regulation of transcriptional output. Epigenetic modifiers, including those that function as AR coregulators, are frequently mutated or aberrantly expressed in prostate cancer and are implicated in disease progression. Some of these modifiers are being investigated as therapeutic targets in several cancer types and could potentially be used to modulate aberrant AR activity in prostate cancer. In this chapter we will summarise the functional role of epigenetic coregulators in AR signalling, their dysregulation during prostate cancer progression and the current status of drugs targeting these enzymes.