NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer.

Hsin-Hsiung Chen,Show-Li Chen,Yeou-Ping Tsao,Szu-Wei Chang,Ping Fan,Hsiang-Po Huang

doi:10.18632/oncotarget.15308

Hsin-Hsiung Chen, Show-Li Chen + Show 4 more

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https://doi.org/10.18632/oncotarget.15308

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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.

Highlights

We determined that the nuclear receptor interaction protein (NRIP; named DCAF6 and IQWD1) is a transcriptional cofactor that enhances androgen receptor (AR)-mediated transcriptional activity [1] and an AR-targeted gene
Our previous study showed that NRIP stabilizes the AR protein and up-regulates the expression of prostatespecific antigen (PSA) [2]
Because the AR is crucial in prostate cancer progression, according to many studies [24, 28], and the PSA test is widely used for prostate cancer screening for men after the age of 50 (National Cancer Institute Website: www.cancer.gov)

Summary

Introduction

We determined that the nuclear receptor interaction protein (NRIP; named DCAF6 and IQWD1) is a transcriptional cofactor that enhances androgen receptor (AR)-mediated transcriptional activity [1] and an AR-targeted gene. NRIP can protect the AR protein from proteasome degradation, the mechanism is unclear [2]. NRIP has been reported to be a member of the DDB1 and Cullin 4 (CUL4)-associated factors (DCAF) family [3]. The NRIP protein is composed of 860 amino acids and contains seven WD-40 repeats and one IQWD1 [1]. We found that NRIP is a human papillomavirus 16 E2-interacting protein and acts as a scaffold to recruit E2 and calcium/calmodulin to prevent polyubiquitination and degradation of E2, resulting in enhanced E2 stability [4]. NRIP is one of the candidate genes involved in cerebral visual impairment, which is causally related to variants of one or multiple genes, including NRIP, with an autosomal recessive transmission pattern [7]

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