Abstract
Transcriptional regulation mediated by the zinc finger protein Snail1 controls early embryogenesis. By binding to the epithelial tumor suppressor CDH1 gene, Snail1 initiates the epithelial–mesenchymal transition (EMT). The EMT generates stem‐like cells and promotes invasiveness during cancer progression. Accordingly, Snail1 mRNA and protein is abundantly expressed in triple‐negative breast cancers with enhanced metastatic potential and phenotypic signs of the EMT. Such high endogenous Snail1 protein levels permit quantitative chromatin immunoprecipitation‐sequencing (ChIP‐seq) analysis. Snail1 associated with 185 genes at cis regulatory regions in the Hs578T triple‐negative breast cancer cell model. These genes include morphogenetic regulators and signaling components that control polarized differentiation. Using the CRISPR/Cas9 system in Hs578T cells, a double deletion of 10 bp each was engineered into the first exon and into the second exon–intron junction of Snail1, suppressing Snail1 expression and causing misregulation of several hundred genes. Specific attention to regulators of chromatin organization provides a possible link to new phenotypes uncovered by the Snail1 loss‐of‐function mutation. On the other hand, genetic inactivation of Snail1 was not sufficient to establish a full epithelial transition to these tumor cells. Thus, Snail1 contributes to the malignant phenotype of breast cancer cells via diverse new mechanisms.
Highlights
During cancer progression, metastasis is a process that contributes to the mortality of cancer patients (Lambert et al, 2017; Nguyen et al, 2009)
EMT is driven by developmental transcription factors (EMTTFs) that control the expression of several genes, often classified into two broad functional groups: the epithelial genes, whose expression is repressed by the EMTTFs, and the mesenchymal genes, whose expression is Abbreviations BMP, bone morphogenetic protein; ChIP, chromatin immunoprecipitation; CPED1, cadherin-like and PC-esterase domain containing 1; CRB1, Crumbs 1; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; EMT-TF, EMT transcription factor; mesenchymal–epithelial transition (MET), mesenchymal– epithelial transition; PPFIA1, protein phosphatase regulatory factor interacting protein a 1; TGFb, transforming growth factor b; ZEB, zinc finger E-box binding homeobox 1
Snail1 can be highly expressed in human breast cancers, which correlates with the grade of malignancy, de-differentiation, and metastatic dissemination (Blanco et al, 2002)
Summary
Metastasis is a process that contributes to the mortality of cancer patients (Lambert et al, 2017; Nguyen et al, 2009). Associated with the invasion cascade are processes of cell differentiation and de-differentiation, which in the case of epithelial carcinomas are best known as epithelial–mesenchymal transition (EMT). Mesenchymal–epithelial transition (MET) (Nieto et al, 2016; Ye and Weinberg, 2015) As such differentiation changes can be reversible or often take place via successive and intermediate stages, they are frequently described with the term epithelial plasticity (Nieto et al, 2016; Ye and Weinberg, 2015).
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