title: A p21-ZEB1 complex inhibits epithelial-mesenchymal transition through the microRNA 183-96-182 cluster.
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.
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Xiao Ling
authors.initials: XL
authors.lastname: Li
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hara
authors.forename: Youngeun
authors.initials: Y
authors.lastname: Choi
authors.forename: Murugan
authors.initials: M
authors.lastname: Subramanian
authors.forename: Princy
authors.initials: P
authors.lastname: Francis
authors.forename: Sven
authors.initials: S
authors.lastname: Bilke
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.forename: Marbin
authors.initials: M
authors.lastname: Pineda
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Ji
authors.initials: J
authors.lastname: Luo
authors.forename: Lalage M
authors.initials: LM
authors.lastname: Wakefield
authors.forename: Thomas
authors.initials: T
authors.lastname: Brabletz
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
authors.forename: Sudha
authors.initials: S
authors.lastname: Sharma
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: Ashish
authors.initials: A
authors.lastname: Lal
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D019012:Integrin beta1; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C533449:MIRN183 microRNA, human; C533896:MIRN200 microRNA, human; C541492:MIRN96 microRNA, human; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D016376:Oligonucleotides, Antisense; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1