miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions

TLDR

p53-mediated inhibition of epithelial‑mesenchymal transition (EMT) has emerged as a novel tumor‑suppressive mechanism that can prevent metastasis. The study aimed to demonstrate that p53 activation down‑regulates the EMT‑inducing transcription factor SNAIL through induction of the miR‑34a/b/c family. p53 induces miR‑34a/b/c, which bind a conserved seed‑matching site in the SNAIL 3′‑UTR to suppress SNAIL, while SNAIL and ZEB1 repress miR‑34 transcription by binding E‑box elements, establishing a double‑negative feedback loop. Loss of miR‑34a/b/c or p53 leads to SNAIL, SLUG, ZEB1, and stemness factor up‑regulation, promoting EMT, migration, invasion, and a metastatic phenotype, whereas ectopic miR‑34a blocks T.

Abstract

Recently, the inhibition of epithelial-mesenchymal-transition (EMT) by p53 has been described as a new mode of tumor suppression which presumably prevents metastasis. Here we report that activation of p53 down-regulates the EMT-inducing transcription factor SNAIL via induction of the miR-34a/b/c genes. Suppression of miR-34a/b/c caused up-regulation of SNAIL and cells displayed EMT markers and related features, as enhanced migration and invasion. Ectopic miR-34a induced mesenchymal-epithelial-transition (MET) and down-regulation of SNAIL, which was mediated by a conserved miR-34a/b/c seed-matching sequence in the SNAIL 3'-UTR. miR-34a also down-regulated SLUG and ZEB1, as well as the stemness factors BMI1, CD44, CD133, OLFM4 and c-MYC. Conversely, the transcription factors SNAIL and ZEB1 bound to E-boxes in the miR-34a/b/c promoters, thereby repressing miR-34a and miR-34b/c expression. Since ectopic miR-34a prevented TGF-β-induced EMT, the repression of miR-34 genes by SNAIL and related factors is part of the EMT program. In conclusion, the frequent inactivation of p53 and/or miR-34a/b/c found in cancer may shift the equilibrium of these reciprocal regulations towards the mesenchymal state and thereby lock cells in a metastatic state.