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

Mai N. Tran, Woonyoung Choi, Matthew F. Wszolek, Neema Navai, I. Ling C. Lee, Giovanni Nitti, Sijin Wen, Elsa R. Flores, Arlene Siefker-Radtke, Bogdan Czerniak, Colin Dinney, Michelle Barton, David J. McConkey

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3275-3288
Number of pages14
JournalJournal of Biological Chemistry
Volume288
Issue number5
DOIs
StatePublished - Feb 1 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Tran, M. N., Choi, W., Wszolek, M. F., Navai, N., Lee, I. L. C., Nitti, G., Wen, S., Flores, E. R., Siefker-Radtke, A., Czerniak, B., Dinney, C., Barton, M., & McConkey, D. J. (2013). The p63 protein isoform ΔNp63α inhibits epithelial-mesenchymal transition in human bladder cancer cells: Role of miR-205. Journal of Biological Chemistry, 288(5), 3275-3288. https://doi.org/10.1074/jbc.M112.408104