Abstract
Evidence has accumulated asserting the importance of cullin-RING (really interesting new gene) ubiquitin ligases (CRLs) and their regulator Cullin-associated neural-precursor-cell-expressed developmentally down-regulated 8 (NEDD8) dissociated protein 1 (Cand1) in various cancer entities. However, the role of Cand1 in prostate cancer (PCa) has not been intensively investigated so far. Thus, in the present study, we aimed to assess the relevance of Cand1 in the clinical and preclinical setting. Immunohistochemical analyses of radical prostatectomy specimens of PCa patients showed that Cand1 protein levels are elevated in PCa compared to benign areas. In addition, high Cand1 levels were associated with higher Gleason Scores, as well as higher tumor recurrence and decreased overall survival. In line with clinical findings, in vitro experiments in different PCa cell lines revealed that knockdown of Cand1 reduced cell viability and proliferation and increased apoptosis, therefore underlining its role in tumor progression. We also found that the cyclin-dependent kinase inhibitor p21 is significantly upregulated upon downregulation of Cand1. Using bioinformatic tools, we detected genes encoding for proteins linked to mRNA turnover, protein polyubiquitination, and proteasomal degradation to be significantly upregulated in Cand1high tumors. Next generation sequencing of PCa cell lines resistant to the anti-androgen enzalutamide revealed that Cand1 is mutated in enzalutamide-resistant cells, however, with little functional and clinically relevant impact in the process of resistance development. To summarize the present study, we found that high Cand1 levels correlate with PCa aggressiveness.
Highlights
Prostate cancer (PCa) remains one of the leading causes of death among men in Western countries [1]
We could show that Cand1 is expressed in the nucleus as well as in the cytoplasm of benign and prostate carcinoma cells
Cand1 was significantly higher expressed in cancer cores compared to benign cores (p < 0.002) (Figure 1A,B)
Summary
Prostate cancer (PCa) remains one of the leading causes of death among men in Western countries [1]. Organ-confined PCa can often be cured predominantly either by radical prostatectomy or by primary radiation therapy, about 15% of patients are diagnosed in a primary metastatic stage [2]. Cancers 2020, 12, 428 patients experience resistance to androgen deprivation therapy (metastatic castration-resistant prostate cancer, mCRPC). In the past five years, several new therapeutic options targeting the androgen receptor (AR)-signaling axis have been developed for this patient population, including the AR-inhibiting agent enzalutamide [5,6]. Response to these drugs, is only temporary, as the majority of treated patients develop drug resistance. The biological mechanisms of drug resistance are still under investigation
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