Endocrine Abstracts

We previously demonstrated that USP12 functions as an AR co-activator by directly deubiquitinating the AR and stabilising its protein levels. Additionally, we showed that USP12 targets the PHLPP AKT phosphatases leading to decreased levels of activated, phosphorylated AKT (pAKT) and as such indirectly stabilises the AR preventing its phosphorylation at serine 213. We further investigated the role of USP12 in prostate cancer by analysing the transcriptome of the LNCaP prostate cancer cell line following depletion of USP12 using siRNA. We discovered that in addition to regulating the AR signalling cascade, USP12 controlled the p53 signalling pathway. Further analysis determined that USP12 directly targets the E3 ubiquitin ligase MDM2, stabilising MDM2 protein and consequently controlling p53 protein levels. Clinical importance of USP12 was confirmed in clinical prostate cancer where increased USP12 was found to be a marker of poor prognosis that correlated with shorter relapse-free survival and reduced overall survival. Additionally we observed that USP12 protein levels were significantly increased in castration resistant prostate cancer (CRPC) patients for two independent clinical cohorts that we investigated, suggesting that USP12 may play a role in the development of CRPC. These findings reveal that a deubiquitinating enzyme that stabilises the AR, namely USP12, additionally controls the p53 pathway and that USP12 protein levels are elevated in prostate cancer and associated with decreased relapse-free survival and overall survival. This identifies USP12 as a promising therapeutic target in prostate cancer and CRPC.

Presenting author: Urszula McClurg, Northern Institute for Cancer Research, Newcastle University, Framlington Place, NE2 4HH, Newcastle upon Tyne, UK. Email: [email protected].