SNAI1 recruits HDAC1 to suppress SNAI2 transcription during epithelial to mesenchymal transition
Journal
Scientific Reports
Journal Volume
9
Journal Issue
1
Pages
8295
Date Issued
2019
Author(s)
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. ? 2019, The Author(s).
SDGs
Other Subjects
cadherin; HDAC1 protein, human; histone; histone deacetylase; histone deacetylase 1; SNAI1 protein, human; SNAI2 protein, human; transcription factor; transcription factor Snail; A-549 cell line; binding site; epithelial mesenchymal transition; female; gene expression regulation; genetic transcription; HEK293 cell line; human; metabolism; ovary tumor; promoter region; treatment outcome; A549 Cells; Binding Sites; Cadherins; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Histone Deacetylase 1; Histone Deacetylases; Histones; Humans; Ovarian Neoplasms; Promoter Regions, Genetic; Snail Family Transcription Factors; Transcription Factors; Transcription, Genetic; Treatment Outcome
Publisher
Nature Publishing Group
Type
journal article