Journal
ONCOTARGET
Volume 6, Issue 35, Pages 37724-37736Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6075
Keywords
androgen receptor; deubiquitination; prostate cancer; Usp12; UAF1
Categories
Funding
- Prostate Cancer UK
- Newcastle Experimental Cancer Medicine Centre (Cancer Research UK) [C9380/A15574]
- Newcastle upon Tyne NHS Trustees
- Newcastle University
- Prostate Cancer UK [CDF12-006] Funding Source: researchfish
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The androgen receptor (AR) is a key transcription factor in the initiation and progression of prostate cancer (PC) and is a major therapeutic target for the treatment of advanced disease. Unfortunately, current therapies are not curative for castration resistant PC and a better understanding of AR regulation could identify novel therapeutic targets and biomarkers to aid treatment of this disease. The AR is known to be regulated by a number of post-translational modifications and we have recently identified the deubiquitinating enzyme Usp12 as a positive regulator of AR. We determined that Usp12 deubiquitinates the AR resulting in elevated receptor stability and activity. Furthermore, Usp12 silencing was shown to reduce proliferation of PC cells. Usp12 is known to require the co-factors Uaf-1 and WDR20 for catalytic activity. In this report we focus further on the role of Uaf-1 and WDR20 in Usp12 regulation and investigate if these co-factors are also required for controlling AR activity. Firstly, we confirm the presence of the Usp12/Uaf-1/WDR20 complex in PC cells and demonstrate the importance of Uaf-1 and WDR20 for Usp12 stabilisation. Consequently, we show that individual silencing of either Uaf-1 or WDR20 is sufficient to abrogate the activity of the Usp12 complex and down-regulate AR-mediated transcription via receptor destabilisation resulting in increased apoptosis and decreased colony forming ability of PC cells. Moreover, expression of both Uaf-1 and WDR20 is higher in PC tissue compared to benign controls. Overall these results highlight the potential importance of the Usp12/Uaf-1/WDR20 complex in AR regulation and PC progression. Highlights: Androgen receptor is a key transcriptional regulator in prostate cancer Usp12/Uaf-1/WDR20 complex plays a crucial role in androgen receptor stability and activity Destabilising an individual Usp12/Uaf-1/WDR20 complex member reduces the protein levels of the whole complex and diminishes androgen receptor activity Protein levels of all members of the Usp12/Uaf-1/WDR20 complex are significantly increased in PC
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