Article

The p63 Protein Isoform Np63 Inhibits Epithelial-Mesenchymal Transition in Human Bladder Cancer Cells: ROLE OF MIR-205

The University of Texas M.D. Anderson Cancer Center, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2012; 288(5). DOI: 10.1074/jbc.M112.408104
Source: PubMed

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, Np63α, promotes miR-205 transcription and controls EMT in human bladder cancer cells. Np63α, E-cadherin and miR-205 were co-expressed in a panel of bladder cancer cell lines (n=28) and a cohort of primary bladder tumors (n=98). Stable knockdown (KD) of Np63α 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 Np63α in the mesenchymal bladder cancer cell line UM-UC3 induced miR-205 and suppressed ZEB1/2. Np63α KD 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 Np63α-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.

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    • "This is achieved by directly repressing the transcription factors ZEB1 and ZEB2 [Gregory et al., 2008], which are central mediators of the EMT. While TP53 has been implicated in the regulation of miR-200c, NTP63 specifically promotes miR-205 transcription in bladder tumors [Tran et al., 2013]. The TP63–miR-205 pathway has been also validated in prostate cancer cells, in which loss of TP63 and its transcriptional target miR-205 enhance metastasis in vivo [Tucci et al., 2012]. "
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    ABSTRACT: In mammals, the p53 family comprises two additional members, p63 and p73 (hereafter referred to as TP53, TP63 and TP73, respectively). The usage of two alternative promoters produces protein variants either with (TA isoforms) or without (ΔN isoforms) the N-terminal transactivation domain. In general, the TA proteins exert TP53-like tumor suppressive activities through their ability to activate a common set of target genes. The ΔN proteins can act as dominant negative inhibitors of the transcriptionally active family members. Additionally, they possess intrinsic specific biological activities due to the presence of alternative transactivation domains, and as a result of engaging a different set of regulators. This review summarizes the current understanding of upstream regulators and downstream effectors of the TP53 family proteins, with particular emphasis on those, which are relevant for their role in tumorigenesis. Furthermore, we highlight the existence of networks and cross-talks amongst the TP53 family members, their modulators as well as the transcriptional targets. This article is protected by copyright. All rights reserved.
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    • "Expression of ∆NTRP63α inhibits EMT triggered by the ∆NTRP63γ isoform in normal mammary epithelial cells (Lindsay et al. 2011) and constrains EMT in bladder cancer cells (Oh et al. 2011). However, it has also been reported that ∆NTRP63α promotes EMT in normal keratinocytes (Tran et al. 2013). While it is known that TRP63 can be expressed in many types of cancer, the percentage of cancers within each type expressing TRP63 varies (Yao and Chen. "
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    • "Numerous studies investigated miRNA profiling signature of bladder carcinomas distinguishing different classes, stages of progression and outcomes (Wiklund et al., 2011; Dip et al., 2012; Wang et al., 2012; Tran et al., 2013). For instance, Neely et al. (2010) noted that a miR- 21:miR-205 expression ratio can be used to distinguish invasive and non-invasive bladder tumors. "
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