title: Deubiquitinating enzyme Usp12 regulates the interaction between the androgen receptor and the Akt pathway.
abstract: The androgen receptor (AR) is a transcription factor involved in prostate cell growth, homeostasis and transformation regulated by post-translational modifications, including ubiquitination. We have recently reported that AR is deubiquitinated and stabilised by Usp12 resulting in increased transcriptional activity. In this study we have investigated the relationship between Usp12, PHLPP and PHLPPL tumour suppressors in the regulation of AR transcriptional activity in prostate cancer (PC). PHLPP and PHLPPL are pro-apoptotic phosphatases that dephosphorylate and subsequently deactivate Akt. Phosphorylated Akt is reported to deactivate AR in PC by phosphorylation at Ser213 and Ser791 leading to ligand dissociation and AR degradation. In contrast, PHLPP- and PHLPPL-mediated dephosphorylation and inactivation of Akt elevates the levels of active AR. In this report we demonstrate that Usp12, in complex with Uaf-1 and WDR20, directly deubiquitinates and stabilises the Akt phosphatases PHLPP and PHLPPL resulting in decreased levels of active pAkt. Decreased pAkt in turn down-regulates AR Ser213 phosphorylation resulting in enhanced receptor stability and transcriptional activity. Additionally, we observe that depleting Usp12 sensitises PC cells to therapies aimed at Akt inhibition irrespectively of their sensitivity to androgen ablation therapy. We propose that Usp12 inhibition could offer a therapeutic alternative for castration resistant prostate cancer.
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
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 NE2 4HH, UK.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Summerscales
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Harle
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
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 NE2 4HH, UK.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C410798:AR protein, human; D009687:Nuclear Proteins; D011944:Receptors, Androgen; C486402:USP12 protein, human; D051057:Proto-Oncogene Proteins c-akt; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases; D043222:Ubiquitin Thiolesterase