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Review
. 2015 May;27(3):172-6.
doi: 10.1097/CCO.0000000000000178.

Implications of ubiquitin ligases in castration-resistant prostate cancer

Jianfei Qi  1 , Lingling Fan, Arif Hussain
Affiliations
Review

Implications of ubiquitin ligases in castration-resistant prostate cancer

Jianfei Qi et al. Curr Opin Oncol. 2015 May.

Abstract

Purpose of review: Significant advances have been made in the study of ubiquitination-mediated regulation of androgen receptor (AR). This review will highlight the latest developments in the mechanisms by which E3 ubiquitin ligases control AR activity, with implications in castration-resistant prostate cancer (CRPC).

Recent findings: Several ubiquitin ligases have been identified to interact with and ubiquitinate AR, and consequently regulate the AR transcriptional programme. Different ubiquitin ligases can use distinct mechanisms to modulate the expression of AR target genes, including local turnover of AR chromatin complex, recruitment of AR coactivators and global AR stability. The expression or activity of ubiquitin ligases can be altered in prostate cancer and thus contribute to the growth of androgen-insensitive prostate cancer cells by modulating the AR transcriptional activity.

Summary: Understanding the regulation of AR transcriptional activity by ubiquitin ligases will contribute to the elucidation of mechanisms underlying AR reactivation that is believed to drive the development of CRPC. Ubiquitin ligases could potentially serve as promising targets for developing therapeutics in the treatment of advanced prostate cancers.

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Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
A. Siah2 ubiquitinates and degrades the AR-NCOR1 complex on AREs of select AR targets. This allows the subsequent recruitment of AR-p300 to activate the transcription of these AR targets. B. RNF6 induces the atypical ubiquitination of AR, and this causes the recruitment of co-activators that have the ubiquitin-binding domain. The AR/co-activator complex binds to AREs of selective AR targets and increases the transcription of these AR targets. C. wild-type (wt) SPOP interacts with AR, leading to the ubiquitination and degradation of AR by the Cul3-Rbx1 ubiquitin ligase complex. Mutant (mut) SPOP cannot interact with AR, resulting in the stabilization of AR and increase of global AR target expression.
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