title: NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer.
abstract: Both nuclear receptor interaction protein (NRIP) and DNA damage binding protein 2 (DDB2) belong to the Cullin 4 (CUL4)-DDB1 binding protein family and are androgen receptor (AR)-interacting proteins. Here, we investigated the expression patterns of the NRIP, DDB2 and AR proteins in human prostate cancer tissues and found that the expression levels of NRIP and AR were higher, but the DDB2 level was lower, in prostate cancer tissues than in non-neoplastic controls, suggesting NRIP as a candidate tumor promoter and DDB2 as a tumor suppressor in prostate cancer. Furthermore, both NRIP and DDB2 shared the same AR binding domain; they were competitors for the AR, but not for DDB1 binding, in the AR-DDB2-DDB1-CUL4A complex. Conclusively, NRIP stabilizes the AR protein by displacing DDB2 from the AR-DDB2 complex. Consistent with our hypothesis, a specific expression pattern with high levels of NRIP and AR, together with a low level of DDB2, was found more frequently in the human prostate cancer tissues with a cribriform pattern than in non-cribriform tumors, suggesting that disruption of the balance between NRIP and DDB2 may change AR protein homeostasis and contribute to pathogenesis in certain aggressive types of prostate cancer.
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Hsin-Hsiung
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, Mackay Memorial Hospital, Taipei 104, Taiwan.
authors.forename: Yeou-Ping
authors.initials: YP
authors.lastname: Tsao
authors.affiliation: Graduate Institute of Medical Genetics and Proteomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Hsiang-Po
authors.initials: HP
authors.lastname: Huang
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Show-Li
authors.initials: SL
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015153:Blotting, Western; D044842:Cullin Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D055550:Protein Stability; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C410798:AR protein, human; D048868:Adaptor Proteins, Signal Transducing; C114234:CUL4A protein, human; D044842:Cullin Proteins; C501825:DCAF6 protein, human; C091435:DDB1 protein, human; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011944:Receptors, Androgen
keywords: AR; Cul4-DDB1; DDB2; NRIP/DCAF6; cribriform prostate cancer