Abstract
Syndecan 1 (SDC-1) is a cell surface proteoglycan with a significant role in cell adhesion, maintaining epithelial integrity. SDC1 expression is inversely related to aggressiveness in prostate cancer (PCa). During epithelial to mesenchymal transition (EMT), loss of epithelial markers is mediated by transcriptional repressors such as SNAIL, SLUG, or ZEB1/2 that bind to E-box promoter sequences of specific genes. The effect of these repressors on SDC-1 expression remains unknown. Here, we demonstrated that SNAIL, SLUG and ZEB1 expressions are increased in advanced PCa, contrarily to SDC-1. SNAIL, SLUG and ZEB1 also showed an inversion to SDC-1 in prostate cell lines. ZEB1, but not SNAIL or SLUG, represses SDC-1 as demonstrated by experiments of ectopic expression in epithelial prostate cell lines. Inversely, expression of ZEB1 shRNA in PCa cell line increased SDC-1 expression. The effect of ZEB1 is transcriptional since ectopic expression of this gene represses SDC-1 promoter activity and ZEB1 binds to the SDC-1 promoter as detected by ChIP assays. An epigenetic mark associated to transcription repression H3K27me3 was bound to the same sites that ZEB1. In conclusion, this study identifies ZEB1 as a key repressor of SDC-1 during PCa progression and point to ZEB1 as a potentially diagnostic marker for PCa.
Highlights
Prostate cancer (PCa) occupies the second place in cancer incidence in men worldwide[1]
This study provides evidence relating the decrease of surface Syndecan 1 (SDC-1) expression and the increase of epithelial to mesenchymal transition (EMT) transcription factors SNAIL, SLUG and ZEB1 in prostate cancer (PCa)
In our research all markers were analyzed in serial samples from the same patients, which gives to these correlations a higher value
Summary
Prostate cancer (PCa) occupies the second place in cancer incidence in men worldwide[1]. Among the stimuli and signaling pathways triggering EMT are the transforming growth factor (TGF-β), fibroblast growth factor (FGF), and epidermal growth factor (EGF), and pathways such as those involving Wnt, Notch, NF-κB, and HIF1/2 All these elements activate transcription factors such as SNAIL, TWIST and ZEB3,5, that repress genes maintaining epithelial integrity (being E-cadherin the most relevant) and induce genes related to the mesenchymal phenotype (matrix metalloproteinases and fibronectin)[5,7,8,9,10,11,12]. SNAIL and ZEB proteins belong to the family of zinc finger type transcription factors that bind directly to the promoter sequences 5′-CACCTG-3′ or CAGGTG (E-box)[13,14] The increase of these transcription factors has been related to aggressiveness and poor prognosis in carcinomas, like PCa15. SDC-1 is expressed mainly in epithelial cells, its distribution is baso-lateral, and influences polarization, morphology and cell positioning[29]
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