A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition

Nam Hee Kim, Hyun Sil Kim, Xiao Yan Li, Inhan Lee, Hyung Seok Choi, Shi Eun Kang, So Young Cha, Joo Kyung Ryu, Dojun Yoon, Eric R. Fearon, R. Grant Rowe, Sanghyuk Lee, Christopher Maher, Stephen J. Weiss, Jong In Yook

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295 Scopus citations

Abstract

Snail1 is a zinc finger transcriptional repressor whose pathological expression has been linked to cancer cell epithelial-mesenchymal transition (EMT) programs and the induction of tissue-invasive activity, but pro-oncogenic events capable of regulating Snail1 activity remain largely uncharacterized. Herein, we demonstrate that p53 loss-of-function or mutation promotes cancer cell EMT by de-repressing Snail1 protein expression and activity. In the absence of wild-type p53 function, Snail1-dependent EMT is activated in colon, breast, and lung carcinoma cells as a consequence of a decrease in miRNA-34 levels, which suppress Snail1 activity by binding to highly conserved 3' untranslated regions in Snail1 itself as well as those of key Snail1 regulatory molecules, including β-catenin, LEF1, and Axin2. Although p53 activity can impact cell cycle regulation, apoptosis, and DNA repair pathways, the EMT and invasion programs initiated by p53 loss of function or mutation are completely dependent on Snail1 expression. These results identify a new link between p53, miR-34, and Snail1 in the regulation of cancer cell EMT programs.

Original languageEnglish
Pages (from-to)417-433
Number of pages17
JournalJournal of Cell Biology
Volume195
Issue number3
DOIs
StatePublished - Oct 31 2011

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    Kim, N. H., Kim, H. S., Li, X. Y., Lee, I., Choi, H. S., Kang, S. E., Cha, S. Y., Ryu, J. K., Yoon, D., Fearon, E. R., Rowe, R. G., Lee, S., Maher, C., Weiss, S. J., & Yook, J. I. (2011). A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. Journal of Cell Biology, 195(3), 417-433. https://doi.org/10.1083/jcb.201103097