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

J 2021

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

MICKOVA, Alena, Gvantsa KHARAISHVILI, Daniela KURFURSTOVA, Mariam GACHECHILADZE, Milan KRAL et. al.

Basic information

Original name

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

Authors

MICKOVA, Alena, Gvantsa KHARAISHVILI, Daniela KURFURSTOVA, Mariam GACHECHILADZE, Milan KRAL, Ondřej VACEK (203 Czech Republic, belonging to the institution), Barbora POKRYVKOVA, Martin MISTRIK, Karel SOUČEK (203 Czech Republic, belonging to the institution) and Jan BOUCHAL (guarantor)

Edition

International Journal of Molecular Sciences, Basel, MDPI, 2021, 1422-0067

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 6.208

RIV identification code

RIV/00216224:14310/21:00121596

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.3390/ijms22062844

UT WoS

000645776800001

Keywords in English

prostate cancer; Skp2 (S-phase kinase-associated protein 2); Slug; immunohistochemistry; multiplex; neddylation

Abstract

V originále

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.

Links

LM2018129, research and development project

Name: Národní infrastruktura pro biologické a medicínské zobrazování Czech-BioImaging

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

MICKOVA, Alena, Gvantsa KHARAISHVILI, Daniela KURFURSTOVA, Mariam GACHECHILADZE, Milan KRAL, Ondřej VACEK, Barbora POKRYVKOVA, Martin MISTRIK, Karel SOUČEK and Jan BOUCHAL. Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade. International Journal of Molecular Sciences. Basel: MDPI, 2021, vol. 22, No 6, p. "2844", 12 pp. ISSN 1422-0067. Available from: https://dx.doi.org/10.3390/ijms22062844.

@article{1769218,
   author = {Mickova, Alena and Kharaishvili, Gvantsa and Kurfurstova, Daniela and Gachechiladze, Mariam and Kral, Milan and Vacek, Ondřej and Pokryvkova, Barbora and Mistrik, Martin and Souček, Karel and Bouchal, Jan},
   article_location = {Basel},
   article_number = {6},
   doi = {http://dx.doi.org/10.3390/ijms22062844},
   keywords = {prostate cancer; Skp2 (S-phase kinase-associated protein 2); Slug; immunohistochemistry; multiplex; neddylation},
   language = {eng},
   issn = {1422-0067},
   journal = {International Journal of Molecular Sciences},
   title = {Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade},
   url = {https://doi.org/10.3390/ijms22062844},
   volume = {22},
   year = {2021}
}

TY  - JOUR
ID  - 1769218
AU  - Mickova, Alena - Kharaishvili, Gvantsa - Kurfurstova, Daniela - Gachechiladze, Mariam - Kral, Milan - Vacek, Ondřej - Pokryvkova, Barbora - Mistrik, Martin - Souček, Karel - Bouchal, Jan
PY  - 2021
TI  - Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade
JF  - International Journal of Molecular Sciences
VL  - 22
IS  - 6
SP  - "2844"
EP  - "2844"
PB  - MDPI
SN  - 14220067
KW  - prostate cancer
KW  - Skp2 (S-phase kinase-associated protein 2)
KW  - Slug
KW  - immunohistochemistry
KW  - multiplex
KW  - neddylation
UR  - https://doi.org/10.3390/ijms22062844
N2  - 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.
ER  -

MICKOVA, Alena, Gvantsa KHARAISHVILI, Daniela KURFURSTOVA, Mariam GACHECHILADZE, Milan KRAL, Ondřej VACEK, Barbora POKRYVKOVA, Martin MISTRIK, Karel SOUČEK and Jan BOUCHAL. Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade. \textit{International Journal of Molecular Sciences}. Basel: MDPI, 2021, vol.~22, No~6, p.~''2844'', 12 pp. ISSN~1422-0067. Available from: https://dx.doi.org/10.3390/ijms22062844.

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