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Abstract
Aberrant activation of epithelial to mesenchymal transition (EMT) associated factors were highly correlated with increased mortality in cancer patients. SNAIL family of transcriptional repressors comprised of three members, each of which were essentially associated with gastrulation and neural crest formation. Among which, SNAI1 and SNAI2 were efficiently induced during EMT and their expressions were correlated with poor clinical outcome in patients with breast, colon and ovarian carcinoma. In an ovarian cancer cell lines panel, we identified that SNAI1 and SNAI2 expressions were mutually exclusive, where SNAI1 predominantly represses SNAI2 expression. Detailed analysis of SNAI2 promoter region revealed that SNAI1 binds to two E-box sequences that mediated transcriptional repression. Through epigenetic inhibitor treatments, we identified that inhibition of histone deacetylase (HDAC) activity in SNAI1 overexpressing cells partially rescued SNAI2 expression. Importantly, we demonstrated a significant deacetylation of histone H3 and significant enrichments of HDAC1 and HDAC2 corepressors in both E-box regions of SNAI2 promoter. Our results suggested that SNAI1 repression on SNAI2 expression was predominantly mediated through the recruitment of the histone deacetylation machinery. Utilization of HDAC inhibitors would require additional profiling of SNAI1 activity and combined targeting of SNAI1 and HDACs might render efficient cancer treatment.
Highlights
Epithelial-Mesenchymal Transition (EMT) is a reversible process, where epithelial cells lose apico-basal polarity and intercellular junctions to form invasive and motile mesenchymal cells or cells with the mesenchymal phenotype, express mesenchymal markers and acquire the front-rear polarity[1]
The SGOCL panel was characterized into four phenotypes constituting the epithelial to mesenchymal transition (EMT) spectrum: Epithelial (E), Intermediate Epithelial (IE), Intermediate Mesenchymal (IM) and Mesenchymal (M) and the delineation for each cell line was determined based on morphological examination and immunofluorescence staining of E-cadherin, Pan-cytokeratin and Vimentin[20]
The results showed a gradual downregulation of epithelial marker, E-cadherin expression and simultaneous upregulation of mesenchymal genes VIM, SNAI1 and SNAI2 in all analysed time points (Supplementary Fig. 1)
Summary
Epithelial-Mesenchymal Transition (EMT) is a reversible process, where epithelial cells lose apico-basal polarity and intercellular junctions to form invasive and motile mesenchymal cells or cells with the mesenchymal phenotype, express mesenchymal markers and acquire the front-rear polarity[1]. Several transcription factors essential during gastrulation have been shown to play central roles in orchestrating the EMT process. The SNAIL family is the best studied EMT transcription factor[4]. Belonging to the zinc finger transcription factor family, SNAI1 and SNAI2 proteins are small in size while maintaining the ability of binding or recruiting several co-regulators. KLF4 and FOXA1 were reported to form reinforcing regulatory loops with SNAI2 in prostate cancer cell lines[15]. Another reciprocal transcriptional repression was reported between SOX3 and SNAI2. A short splice variant of the Per-Arnt-Sim transcription factor Singleminded-2 (SIM2), has been shown to repress SNAI2 in a dose-dependent manner in breast cancer cell lines[17]. There is scattered information regarding how SNAI1 and SNAI2 regulate each other and how SNAI1 and SNAI2 is chosen under different contexts to execute exclusive functions
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