Genomewide binding of transcription factor Snail1 in triple‐negative breast cancer cells

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.

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

“…Genome-wide screening of ZEB1 targets using TNBC cell line Hs578T revealed more than 2,000 genes that are positively or negatively regulated by this transcription factor. In the context of plasticity, ZEB1 contributed to the regulation of cell polarity via DLG2 and FAT3 proteins, cell-to-cell adhesion via transmembrane protein TENM2 or anchorage-independent growth through interaction with metalloproteinase inhibitor TIMP3 (Maturi et al, 2018). Moreover, strong evidence indicates that ZEB1, but not Snail or Slug, is the master regulator of phenotypic as well as metabolic plasticity of pancreatic cells, affecting cancer cell dissemination and metastasis (Krebs et al, 2017).…”

SNAIL1 employs β‐Catenin‐LEF1 complexes to control colorectal cancer cell invasion and proliferation

“…Upon induction, core EMT TFs trigger widespread alterations in epithelial and mesenchymal gene expression. Intriguingly, the number of genes that are deregulated in the presence of core EMT TFs vastly exceeds the number of their direct targets . Therefore, an important question becomes to decipher the molecular mechanisms whereby the full extent of EMT‐associated transcriptional changes is brought about.…”

“…Intriguingly, the number of genes that are deregulated in the presence of core EMT TFs vastly exceeds the number of their direct targets. 4 Therefore, an important question becomes to decipher the molecular mechanisms whereby the full extent of EMTassociated transcriptional changes is brought about. A potential scenario for this could be that core EMT TFs reside at the apex of a regulatory hierarchy to prompt changes in the activity of an expanding set of downstream effectors, whereby the full EMT process gradually unfolds.…”

G9a and histone deacetylases are crucial for Snail2‐mediated E‐cadherin repression and metastasis in hepatocellular carcinoma

“…Snail1 has been reported to induce EMT in MDCK and breast cancer cells by suppressing E‐cadherin expression . Moreover, Snail1 can promote cell motility and invasive activity by regulating EMT and enhancing some features of cancer stem cells . As a transcriptional repressor similar to Snail1, Snail2 is known to directly repress transcription from the E‐cadherin promoter and thereby promote disassembly of cell‐cell contacts .…”

“…[13][14][15] Moreover, Snail1 can promote cell motility and invasive activity by regulating EMT and enhancing some features of cancer stem cells. 16,17 As a transcriptional repressor similar to Snail1, Snail2 is known to directly repress transcription from the E-cadherin promoter and thereby promote disassembly of cell-cell contacts. 10 However, few studies have investigated the relationship between Snail and EMT in HCC, and its implications in tumor progression.…”