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Open AccessArticle

The Impact of Cand1 in Prostate Cancer

1
Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria
2
Laboratory for Immunotherapy, Department of Internal Medicine II, Medical University of Innsbruck, 6020 Innsbruck, Austria
3
Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
4
Department of Internal Medicine V, Medical University of Innsbruck, 6020 Innsbruck, Austria
5
Department of Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(2), 428; https://doi.org/10.3390/cancers12020428
Received: 20 January 2020 / Revised: 7 February 2020 / Accepted: 9 February 2020 / Published: 12 February 2020
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. View Full-Text
Keywords: Prostate cancer; Cand1; cancer aggressiveness; survival; tumor recurrence; mutation; enzalutamide resistance Prostate cancer; Cand1; cancer aggressiveness; survival; tumor recurrence; mutation; enzalutamide resistance
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Eigentler, A.; Tymoszuk, P.; Zwick, J.; Schmitz, A.A.; Pircher, A.; Kocher, F.; Schlicker, A.; Lesche, R.; Schäfer, G.; Theurl, I.; Klocker, H.; Heidegger, I. The Impact of Cand1 in Prostate Cancer. Cancers 2020, 12, 428.

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