Deubiquitinating Enzyme Usp12 Is a Novel Co-activator of the Androgen Receptor

Abstract

Background: Androgen receptor (AR) is the principle therapeutic target in prostate cancer. Result: We have established that Usp12 deubiquitinates and stabilizes the AR resulting in increased transcriptional and proproliferative activity. Conclusion:We have identified Usp12 to be a novel positive regulator of AR. Significance: Usp12 presents a therapeutic target upstream of AR that could enable bypassing the limitations of therapeutics aimed specifically at AR.

Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20

“…USP1, the founding member of this USP subfamily, plays an essential role in the Fanconi anemia (FA) DNA repair pathways by removing mono-ubiquitin from FANCD2 and PCNA (Huang et al, 2006; Kim and D’Andrea, 2012; Moldovan and D’Andrea, 2009; Nijman et al, 2005a). USP12 and USP46, on the other hand, are two closely related DUBs responsible for deubiquitinating and stabilizing a variety of protein substrates in cell signaling (Burska et al, 2013; Dahlberg and Juo, 2014; Gangula and Maddika, 2013; Joo et al, 2011; Li et al, 2013; McClurg et al, 2014; Moretti et al, 2012). USP12, in particular, is implicated in prostate cancer as a co-activator of the androgen receptor and is overexpressed in colorectal carcinoma driven by a focally amplified super-enhancer (Burska et al, 2013; Zhang et al, 2016).…”

“…USP12 and USP46, on the other hand, are two closely related DUBs responsible for deubiquitinating and stabilizing a variety of protein substrates in cell signaling (Burska et al, 2013; Dahlberg and Juo, 2014; Gangula and Maddika, 2013; Joo et al, 2011; Li et al, 2013; McClurg et al, 2014; Moretti et al, 2012). USP12, in particular, is implicated in prostate cancer as a co-activator of the androgen receptor and is overexpressed in colorectal carcinoma driven by a focally amplified super-enhancer (Burska et al, 2013; Zhang et al, 2016). Recent affinity-based analyses have identified an evolutionarily conserved WD40-repeat containing protein, UAF1 (USP1-associated factor 1), which can directly interact with all three USPs (Cohn et al, 2007; Sowa et al, 2009).…”

“…Although in isolation these three USP enzymes are mostly inactive, their isopeptidase activities are strongly enhanced upon binding to UAF1 (Cohn et al, 2009; Dahlberg and Juo, 2014; Gangula and Maddika, 2013). Interestingly, USP12 and USP46, but not USP1, can be independently activated by another WD40-repeat containing protein, WDR20 (Burska et al, 2013; Dahlberg and Juo, 2014; Kee et al, 2010; McClurg et al, 2014). Together, UAF1 and WDR20 are able to synergistically stimulate the enzymatic activities of USP12 and USP46 to a peak level.…”

The Deubiquitinating Enzyme USP7 Regulates Androgen Receptor Activity by Modulating Its Binding to Chromatin

“…Deubiquitination of AR is also critical for its activity and stability. The USP12, which is a deubiquitinating enzyme, is co-localized with AR in the cytoplasm and also can promote AR transcriptional activity by opposing the ubiquitindependent degradation of ARs (20). USP26 also can counteract AR activation and degradation by reversing MDM2-mediated ubiquitination (21).…”

Epithelial cell ADAM17 activation by Helicobacter pylori: role of ADAM17 C-terminus and Threonine-735 phosphorylation

“…For Quantitative Real-Time Polymerase chain reaction (qRT-PCR) RNA isolation and cDNA synthesis was as above. Quantitative RT-PCR and data analysis was performed as described previously using SYBR Green I [37]. Primers used are listed in Table 1.…”