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Zeb1 and S nail1 engage mi R ‐200f transcriptional and epigenetic regulation during EMT
Author(s) -
DíazLópez Antonio,
DíazMartín Juan,
MorenoBueno Gema,
Cuevas Eva P.,
Santos Vanesa,
Olmeda David,
Portillo Francisco,
Palacios José,
Cano Amparo
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29177
Subject(s) - epigenetics , epithelial–mesenchymal transition , biology , dna methylation , microrna , metastasis , transcription factor , downregulation and upregulation , microbiology and biotechnology , mesenchymal stem cell , cancer research , genetics , cancer , gene expression , gene
Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT‐TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post‐transcriptionally downregulated by several miRNAs, as the miR‐200 family. The specific or redundant role of different EMT‐TFs and their functional interrelations are not fully understood. To study the interplay between different EMT‐TFs, comprehensive gain and loss‐of‐function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR‐200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR‐200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT‐TFs in miR‐200 family regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo .