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

Abstract

Skp2 is a crucial component of SCF Skp2 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.

Tumor Microenvironment in Prostate Cancer: Toward Identification of Novel Molecular Biomarkers for Diagnosis, Prognosis, and Therapy Development

“…The stemness phenotype was reduced in cells with a silenced Skp2 . Moreover, Skp2 downregulation diminished the subpopulation of CD44 +/ CD24 − PCSC, which further supports the notable involvement of Skp2 in PCa stemness ( Simeckova et al, 2019 ). Using lineage retracing, Yoo et al identified a subpopulation of Bmi1+ Sox2+ CRPC cells as a potential source of in vivo disease recurrence.…”

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

“…We have previously shown that a high Gleason score is associated with higher Skp2 and lower E-cadherin expression in a retrospective cohort of 101 patients ( Table 1 ) [ 17 ].…”

“…Next, we aimed to perform functional experiments, and we first made a screen of Skp2, Slug, and other proteins in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. We have already reported that high Skp2 expression is associated with a mesenchymal phenotype and increased tumorigenic potential of DU145 prostate cancer cells [ 17 ]. These cells had a very low expression of Slug ( Figure 3 ), which is in concordance with other studies [ 8 ].…”

“…The epithelial and mesenchymal sublines were established from sorted single-cell clones derived from Trop-2-positive or Trop-2-negative DU145 populations, as previously described [ 40 ]. The AmpFLSTR Identifiler PCR Amplification Kit (ThermoFisher, Waltham, MA, USA) was used to verify the origin of cell lines [ 17 ].…”

The Impact of [C16Pyr][Amp] on the Aggressiveness in Breast and Prostate Cancer Cell Lines

“…SKP2 is an oncogene that encodes a protein that regulates cell cycle entry and G 1 /S transition through a negative feedback loop targeting p21 and p27 degradation, thereby inhibiting cyclin-dependent kinases [ 85 , 86 ]. SKP2 overexpression has been already described in BrCa and PCa, contributing to the development and proliferation of these tumors, the acquisition of a mesenchymal phenotype, and the resistance to radio- and chemotherapy [ 87 , 88 , 89 , 90 ], being a potential therapeutic target [ 73 ]. Accordingly, [C16Pyr][Amp] showed promising results by reducing the SKP2 mRNA levels in the BrCa and PCa cell lines.…”