Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, wh...

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Main Authors: Alena Mickova, Gvantsa Kharaishvili, Daniela Kurfurstova, Mariam Gachechiladze, Milan Kral, Ondrej Vacek, Barbora Pokryvkova, Martin Mistrik, Karel Soucek, Jan Bouchal
Format: Article
Language:English
Published: MDPI AG 2021-03-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/22/6/2844
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spelling doaj-f1db5d01f69e433385fe523cc89901b52021-03-12T00:01:55ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01222844284410.3390/ijms22062844Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation BlockadeAlena Mickova0Gvantsa Kharaishvili1Daniela Kurfurstova2Mariam Gachechiladze3Milan Kral4Ondrej Vacek5Barbora Pokryvkova6Martin Mistrik7Karel Soucek8Jan Bouchal9Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 779 00 Olomouc, Czech RepublicDepartment of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 779 00 Olomouc, Czech RepublicDepartment of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 779 00 Olomouc, Czech RepublicDepartment of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 779 00 Olomouc, Czech RepublicDepartment of Urology, University Hospital, 779 00 Olomouc, Czech RepublicDepartment of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech RepublicDepartment of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 252 50 Vestec, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech RepublicDepartment of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech RepublicDepartment of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, 779 00 Olomouc, Czech RepublicProstate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.https://www.mdpi.com/1422-0067/22/6/2844prostate cancerSkp2 (S-phase kinase-associated protein 2)Slugimmunohistochemistrymultiplexneddylation
collection DOAJ
language English
format Article
sources DOAJ
author Alena Mickova
Gvantsa Kharaishvili
Daniela Kurfurstova
Mariam Gachechiladze
Milan Kral
Ondrej Vacek
Barbora Pokryvkova
Martin Mistrik
Karel Soucek
Jan Bouchal
spellingShingle Alena Mickova
Gvantsa Kharaishvili
Daniela Kurfurstova
Mariam Gachechiladze
Milan Kral
Ondrej Vacek
Barbora Pokryvkova
Martin Mistrik
Karel Soucek
Jan Bouchal
Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade
International Journal of Molecular Sciences
prostate cancer
Skp2 (S-phase kinase-associated protein 2)
Slug
immunohistochemistry
multiplex
neddylation
author_facet Alena Mickova
Gvantsa Kharaishvili
Daniela Kurfurstova
Mariam Gachechiladze
Milan Kral
Ondrej Vacek
Barbora Pokryvkova
Martin Mistrik
Karel Soucek
Jan Bouchal
author_sort Alena Mickova
title Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade
title_short Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade
title_full Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade
title_fullStr Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade
title_full_unstemmed Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade
title_sort skp2 and slug are coexpressed in aggressive prostate cancer and inhibited by neddylation blockade
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1661-6596
1422-0067
publishDate 2021-03-01
description Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.
topic prostate cancer
Skp2 (S-phase kinase-associated protein 2)
Slug
immunohistochemistry
multiplex
neddylation
url https://www.mdpi.com/1422-0067/22/6/2844
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