title: Ubiquitin-specific protease 12 interacting partners Uaf-1 and WDR20 are potential therapeutic targets in prostate cancer.
abstract: 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.
  
  
  CONCLUSIONS
  • 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.
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Urszula L
authors.initials: UL
authors.lastname: McClurg
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Harle
authors.affiliation: Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Arash
authors.initials: A
authors.lastname: Nabbi
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Amanda
authors.initials: A
authors.lastname: Batalha-Pereira
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Scott
authors.initials: S
authors.lastname: Walker
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Kelly
authors.initials: K
authors.lastname: Coffey
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Luke
authors.initials: L
authors.lastname: Gaughan
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Stuart R C
authors.initials: SR
authors.lastname: McCracken
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D064570:Ubiquitin-Specific Proteases / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D064570:Ubiquitin-Specific Proteases; C410798:AR protein, human; C526165:WDR48 protein, human; C549040:WDR20 protein, human
keywords: UAF1; Usp12; androgen receptor; deubiquitination; prostate cancer