Endocrine Abstracts (2016) 42 P21 | DOI: 10.1530/endoabs.42.P21

Investigating the role of SUMOylation of androgen receptor splice variants by SUMO1 in castration resistant prostate cancer

Evangelia E Kounatidou & Luke Gaughan

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.

Prostate cancer (PC) is currently the most commonly diagnosed non-cutaneous cancer affecting UK men. Androgen deprivation therapy (ADT) has traditionally been used as the gold standard treatment for advanced PC. Despite the initial response to androgen ablation, tumours relapse and become refractory to clinically approved anti-androgens, resulting in castration-resistant PC (CRPC). In CRPC, androgen receptor (AR) signalling is inappropriately restored by AR splice variants (AR-Vs). AR-Vs lack the C-terminal ligand-binding domain, that is the target of anti-androgens, but retain the N-terminal transactivation domain and DNA-binding domain, and are thus capable of sustaining the androgenic signalling programme in castrate conditions, remaining unchallenged by the current anti-AR agents. Regulatory post-translational modifications are highly implicated in PC progression. Modification of the full-length AR (FL-AR) by SUMO1 compromises AR transcriptional activity and cell proliferation in vitro. Consistent with FL-AR, we report that the CRPC-relevant AR-V7 and V1/2/3/2b variants are modified by SUMO1 at lysines 386 and 520 within the N-terminal domain. K386 is the major site for polySUMOylation, whilst K520 is likely the substrate for monoSUMOylation. The presence of other potential acceptor lysines as well as the role of AR-V SUMOylation in CRPC are currently being investigated. A comprehensive understanding of how these AR-Vs are regulated by upstream signals such as SUMOylation is of great significance in the finding of more effective treatments. This project aims to highlight key regulatory processes of AR-Vs and conceivably identify potential targets that may be exploited in the clinic to greatly benefit patients with advanced PC.

Presenting author: Evangelia K. Kounatidou. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK. Email: e.e.kounatidou2@ncl.ac.uk.

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