TY - JOUR
T1 - A P21-ZEB1 complex inhibits epithelial-mesenchymal transition through the microRNA 183-96-182 cluster
AU - Li, Xiao Ling
AU - Hara, Toshifumi
AU - Choi, Youngeun
AU - Subramanian, Murugan
AU - Francis, Princy
AU - Bilke, Sven
AU - Walker, Robert L.
AU - Pineda, Marbin
AU - Zhu, Yuelin
AU - Yang, Yuan
AU - Luo, Ji
AU - Wakefield, Lalage M.
AU - Brabletz, Thomas
AU - Park, Ben Ho
AU - Sharma, Sudha
AU - Chowdhury, Dipanjan
AU - Meltzer, Paul S.
AU - Lal, Ashish
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
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U2 - 10.1128/MCB.01043-13
DO - 10.1128/MCB.01043-13
M3 - Article
C2 - 24277930
AN - SCOPUS:84892457520
SN - 0270-7306
VL - 34
SP - 533
EP - 550
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 3
ER -