High Skp2 expression is associated with a mesenchymal phenotype and increased tumorigenic potential of prostate cancer cells

Šárka Šimečková,Gvantsa Kharaishvili,Karel Souček,Milan Král,Tereza Suchánková,Jiřina Procházková,Petr Beneš,Jan Bouchal,Radek Fedr,Eva Slabáková,Ján Remšík,Zuzana Kahounová

doi:10.1038/s41598-019-42131-y

Abstract

Skp2 is a crucial component of SCFSkp2 E3 ubiquitin ligase and is often overexpressed in various types of cancer, including prostate cancer (PCa). The epithelial-to-mesenchymal transition (EMT) is involved in PCa progression. The acquisition of a mesenchymal phenotype that results in a cancer stem cell (CSC) phenotype in PCa was described. Therefore, we aimed to investigate the expression and localization of Skp2 in clinical samples from patients with PCa, the association of Skp2 with EMT status, and the role of Skp2 in prostate CSC. We found that nuclear expression of Skp2 was increased in patients with PCa compared to those with benign hyperplasia, and correlated with high Gleason score in PCa patients. Increased Skp2 expression was observed in PCa cell lines with mesenchymal and CSC-like phenotype compared to their epithelial counterparts. Conversely, the CSC-like phenotype was diminished in cells in which SKP2 expression was silenced. Furthermore, we observed that Skp2 downregulation led to the decrease in subpopulation of CD44+CD24− cancer stem-like cells. Finally, we showed that high expression levels of both CD24 and CD44 were associated with favorable recurrence-free survival for PCa patients. This study uncovered the Skp2-mediated CSC-like phenotype with oncogenic functions in PCa.

Highlights

Prostate cancer is the second leading cause of cancer-related deaths in men in western countries[1]
High nuclear Skp[2] expression and mesenchymal phenotype is associated with high Gleason score in patients with prostate cancer
We found that the mesenchymal phenotype of prostate cancer cells was accompanied by an increase in Skp[2] levels in all selected pairs of cell lines (Fig. 2B, Supplementary Fig. 2C)

Summary

Introduction

Prostate cancer is the second leading cause of cancer-related deaths in men in western countries[1]. The epithelial-to-mesenchymal transition (EMT) is a physiological process during embryogenesis that may become reactivated in cancer It is characterized by the loss of cell-to-cell adhesion and apical-basal polarity, and the gain of migratory behaviour[2]. The acquisition of a mesenchymal phenotype, concomitant with a cancer stem cell (CSC) phenotype, in prostate cancer has been shown previously[4,5,6]. The roles of Skp[2] in both EMT and cancer stem-like cells in prostate cancer have not been fully elucidated. A mesenchymal phenotype was found to be associated with characteristics of cancer stem-like cells, including a DU 145 cell phenotype that was altered after Skp[2] downregulation

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