The p63 protein isoform ΔNp63α inhibits epithelial-mesenchymal transition in human bladder cancer cells: role of MIR-205

• Published in: The Journal of biological chemistry 2013-02, Vol.288 (5), p.3275-3288
• Main Authors: Tran, Mai N, Choi, Woonyoung, Wszolek, Matthew F, Navai, Neema, Lee, I-Ling C, Nitti, Giovanni, Wen, Sijin, Flores, Elsa R, Siefker-Radtke, Arlene, Czerniak, Bogdan, Dinney, Colin, Barton, Michelle, McConkey, David J
• Format: Article
• Language: English
• Subjects: Base Sequence; Biomarkers, Tumor - metabolism; Cell Line, Tumor; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic; Homeodomain Proteins - metabolism; Humans; Kaplan-Meier Estimate; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Bases of Disease; Molecular Sequence Data; Protein Binding - genetics; Protein Isoforms - genetics; Protein Isoforms - metabolism; Repressor Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Treatment Outcome; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urothelium - metabolism; Urothelium - pathology; Zinc Finger E-box Binding Homeobox 2; Zinc Finger E-box-Binding Homeobox 1
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.408104

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.