The Cell Cycle Inhibitor p21 Regulates microRNAs and Controls Epithelial-Mesenchymal Transition

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	MOLBIO-7

Authors

• X.L. Li
• P. Francis
• M. Pineda
• S. Bilke
• M. Subramanian
• T. Hara
• P.S. Meltzer
• A. Lal

Abstract

p21 is a key downstream effector of p53. In addition to its role in cell cycle control, p21 has also been shown to regulate gene expression. microRNAs are small regulatory RNAs that influence several steps of tumorigenesis including the epithelial-mesenchymal transition (EMT). Because the mechanism of transcription of miRNAs is similar to protein-coding genes, we hypothesized that p21 directly regulates the expression of specific miRNAs. Indeed, using deep sequencing from a pair of isogenic HCT116 cells with targeted deletion of p21 or wild-type p21, we identified ninety p21-regulated miRNAs including miR-200 and miR-183-96-182 cluster. Here, we show that targeted deletion of p21 induces EMT and that introduction of the miR-183-96-182 cluster miRNAs in p21-deficient cells induces a MET (mesenchymal-epithelial transition) program by suppressing the expression of SLUG and ZEB1, and increasing the levels of E-cadherin. Moreover, introduction of miR-183 and miR-96 in p21-/- cells significantly reduces cell migration and invasion. Furthermore, we demonstrate that the switch to a mesenchymal phenotype and changes in miRNA expression is not restricted to HCT116 cells but is also observed in MCF10A cells upon acute loss of p21. Taken together, we have uncovered a novel role of p21 in regulating miRNA expression and controlling EMT.

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