title: The p63 protein isoform ΔNp63α inhibits epithelial-mesenchymal transition in human bladder cancer cells: role of MIR-205.
abstract: Epithelial-mesenchymal transition (EMT) is a physiological process that plays important roles in tumor metastasis, "stemness," and drug resistance. EMT is typically characterized by the loss of the epithelial marker E-cadherin and increased expression of EMT-associated transcriptional repressors, including ZEB1 and ZEB2. The miR-200 family and miR-205 prevent EMT through suppression of ZEB1/2. p53 has been implicated in the regulation of miR-200c, but the mechanisms controlling miR-205 expression remain elusive. Here we report that the p53 family member and p63 isoform, ΔNp63α, promotes miR-205 transcription and controls EMT in human bladder cancer cells. ΔNp63α, E-cadherin and miR-205 were coexpressed in a panel of bladder cancer cell lines (n = 28) and a cohort of primary bladder tumors (n = 98). Stable knockdown of ΔNp63α in the "epithelial" bladder cancer cell line UM-UC6 decreased the expression of miR-205 and induced the expression of ZEB1/2, effects that were reversed by expression of exogenous miR-205. Conversely, overexpression of ΔNp63α in the "mesenchymal" bladder cancer cell line UM-UC3 induced miR-205 and suppressed ZEB1/2. ΔNp63α knockdown reduced the expression of the primary and mature forms of miR-205 and the miR-205 "host" gene (miR-205HG) and decreased binding of RNA Pol II to the miR-205HG promoter, inhibiting miR-205HG transcription. Finally, high miR-205 expression was associated with adverse clinical outcomes in bladder cancer patients. Together, our data demonstrate that ΔNp63α-mediated expression of miR-205 contributes to the regulation of EMT in bladder cancer cells and identify miR-205 as a molecular marker of the lethal subset of human bladder cancers.
authors.affiliation: Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77054, USA.
authors.forename: Mai N
authors.initials: MN
authors.lastname: Tran
authors.forename: Woonyoung
authors.initials: W
authors.lastname: Choi
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Wszolek
authors.forename: Neema
authors.initials: N
authors.lastname: Navai
authors.forename: I-Ling C
authors.initials: IL
authors.lastname: Lee
authors.forename: Giovanni
authors.initials: G
authors.lastname: Nitti
authors.forename: Sijin
authors.initials: S
authors.lastname: Wen
authors.forename: Elsa R
authors.initials: ER
authors.lastname: Flores
authors.forename: Arlene
authors.initials: A
authors.lastname: Siefker-Radtke
authors.forename: Bogdan
authors.initials: B
authors.lastname: Czerniak
authors.forename: Colin
authors.initials: C
authors.lastname: Dinney
authors.forename: Michelle
authors.initials: M
authors.lastname: Barton
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
mesh_terms: D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology*; D019459:Urothelium / Q000378:metabolism / Q000473:pathology; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D035683:MicroRNAs; D020033:Protein Isoforms; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; C534425:MIR205, human; C115051:TP63 protein, human; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human