Androgen receptor co-regulatory proteins as alternative therapeutic targets in prostate cancer


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Craig Robson
Northern Institute for Cancer Research, University of Newcastle, UK

Abstract

The androgen receptor is a critical transcriptional regulator involved in prostate cancer development and progression, highlighting the androgen-androgen receptor axis as the primary target for therapeutic intervention. These treatments are however ineffective due to the activation of the androgen receptor signalling cascade via alternative signalling pathways that results in the incurable castrate resistant form of the disease.

The androgen receptor signalling pathway is extremely tightly controlled and multiple co-regulator proteins can modulate its transcriptional activity through post-translational modifications. Receptor phosphorylation, acetylation, methylation, ubiquitylation and sumoylation represent the major characterised post-translational modifications that impact on androgen receptor activity. Although these modifications are generally studied as individual events, it is increasingly evident that interplay exists where these modifications may cooperate together or oppose each other's action in a post-translational signalling pathway. Several groups, including our own have demonstrated that these epigenetic protein modifications play important roles in androgen receptor stability, protein-protein interactions, cellular localisation and transcriptional activity. Recent research, including application of siRNA screening, proteomic analysis and codon switch experiments have aided the identification of key receptor co-regulators, revealed multiple new amino acid sites that are subject to modification and interrogated their contribution to androgen receptor signalling.

The repertoire of androgen receptor co-regulators has now substantially expanded and the many examples of mis-regulation of these co-regulators during prostate cancer pathogenesis identifies a large group of druggable proteins whose enzymatic activities may be modulated to consequently reduce androgen receptor activity. This will provide new treatments for patients with advanced prostate cancer who become resistant to current therapies.