The p63 Protein Isoform ΔNp63α Inhibits Epithelial-Mesenchymal Transition in Human Bladder Cancer Cells

• 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: Bladder Cancer; Cancer Biology; Cell Invasion; Epithelial Mesenchymal Transition; MicroRNA; miR-205; p63; ZEB1; ZEB2
• 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. Background: ΔNp63 expression correlates with an epithelial phenotype and adverse clinical outcome. Results: ΔNp63α suppressed ZEB1/2 and invasion in part by promoting miR-205 transcription, and tumor miR-205 expression is a marker of poor survival. Conclusion: ΔNp63α inhibits EMT in part via miR-205. Significance: We show that ΔNp63α directly regulates miR-205 and that these effects contribute to EMT suppression. The results provide important insight into the biology of lethal bladder cancer.