NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer
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Hsin-Hsiung Chen1,*, Ping Fan1,*, Szu-Wei Chang1,*, Yeou-Ping Tsao2, Hsiang-Po Huang3, Show-Li Chen1
1Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
2Department of Ophthalmology, Mackay Memorial Hospital, Taipei 104, Taiwan
3Graduate Institute of Medical Genetics and Proteomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan
*These authors have contributed equally to this work
Show-Li Chen, email: [email protected]
Hsiang-Po Huang, email: [email protected]
Keywords: NRIP/DCAF6, DDB2, AR, Cul4-DDB1, cribriform prostate cancer
Received: October 27, 2016 Accepted: January 27, 2017 Published: February 14, 2017
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.
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