A P21-ZEB1 complex inhibits epithelial-mesenchymal transition through the microRNA 183-96-182 cluster

Xiao Ling Li, Toshifumi Hara, Youngeun Choi, Murugan Subramanian, Princy Francis, Sven Bilke, Robert L. Walker, Marbin Pineda, Yuelin Zhu, Yuan Yang, Ji Luo, Lalage M. Wakefield, Thomas Brabletz, Ben Ho Park, Sudha Sharma, Dipanjan Chowdhury, Paul S. Meltzer, Ashish Lal

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Abstract

The tumor suppressor P21 acts as a cell cycle inhibitor and has also been shown to regulate gene expression by functioning as a transcription corepressor. Here, we identified P21-regulated microRNAs (miRNAs) by sequencing small RNAs from isogenic P21+/+ and P21-/- cells. Three abundant miRNA clusters, miR-200b-200a-429, miR-200c-141, and miR-183-96-182, were downregulated in P21-deficient cells. Consistent with the known function of the miR-200 family and P21 in inhibition of the epithelial- mesenchymal transition (EMT), we observed EMT upon loss of P21 in multiple model systems. To explore a role of the miR- 183-96-182 cluster in EMT, we identified its genome-wide targets and found that miR-183 and miR-96 repressed common targets, including SLUG, ZEB1, ITGB1, and KLF4. Reintroduction of miR-200, miR-183, or miR-96 in P21+/+ cells inhibited EMT, cell migration, and invasion. Conversely, antagonizing miR-200 and miR-183-96-182 cluster miRNAs in P21-/- cells increased invasion and elevated the levels of VIM, ZEB1, and SLUG mRNAs. Furthermore, we found that P21 forms a complex with ZEB1 at the miR-183-96-182 cluster promoter to inhibit transcriptional repression of this cluster by ZEB1, suggesting a reciprocal feedback loop.

Original languageEnglish
Pages (from-to)533-550
Number of pages18
JournalMolecular and Cellular Biology
Volume34
Issue number3
DOIs
Publication statusPublished - 1 Feb 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Li, X. L., Hara, T., Choi, Y., Subramanian, M., Francis, P., Bilke, S., Walker, R. L., Pineda, M., Zhu, Y., Yang, Y., Luo, J., Wakefield, L. M., Brabletz, T., Park, B. H., Sharma, S., Chowdhury, D., Meltzer, P. S., & Lal, A. (2014). A P21-ZEB1 complex inhibits epithelial-mesenchymal transition through the microRNA 183-96-182 cluster. Molecular and Cellular Biology, 34(3), 533-550. https://doi.org/10.1128/MCB.01043-13