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


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.
    Preview · Article · Jun 2014 · Human Mutation
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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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    ABSTRACT: Trp63, founding member of the Trp53 family, contributes to epithelial differentiation and is expressed in breast neoplasia. Trp63 features two distinct promoters yielding specific mRNAs encoding two major TRP63 isoforms, a transactivating transcription factor and a dominant negative isoform. Specific TRP63 isoforms are linked to cell cycle arrest, apoptosis, survival and epithelial mesenchymal transition. Although TRP63 overexpression in cultured cells is used to elucidate functions, little is known about Trp63 regulation in normal and cancerous mammary tissue. This study used ChIP-seq to interrogate transcription factor binding and histone modifications of the Trp63 locus in mammary tissue and RNA-seq and immunohistochemistry to gauge gene expression. H3K4me2 and H3K4me3 marks coincided only with the proximal promoter, supporting RNA-seq data showing the predominance of the dominant negative isoform. STAT5 bound specifically to the Trp63 proximal promoter and Trp63 mRNA levels were elevated upon deleting STAT5 from mammary tissue, suggesting its role as a negative regulator. The dominant negative TRP63 isoform was localized to nuclei of basal mammary epithelial cells throughout reproductive cycles, and retained in a majority of the triple negative cancers generated from loss of full-length BRCA1. Increased expression of dominant negative isoforms was correlated with developmental windows of increased progesterone receptor binding to the proximal Trp63 promoter and decreased expression during lactation was correlated with STAT5 binding to the same region. TRP63 is present in the majority of triple negative cancers resulting from loss of BRCA1 but diminished in less differentiated cancer subtypes and in cancer cells undergoing epithelial mesenchymal transition.
    Full-text · Article · Apr 2014 · Endocrine Related Cancer
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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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    ABSTRACT: The recent discovery of tiny microRNAs (miRNAs) has brought about awareness of a new class of regulators of diverse pathways in many physiological and pathological processes, such as tumorigenesis. They modulate gene expression by targeting plethora of mRNAs, mostly reducing the protein yield of a targeted mRNA. With accumulation of information on characteristics of miR-205, complex and in some cases converse roles of miR-205 in tumor initiation, progression and metastasis are emerging. miR-205 acts either as an oncogene via facilitating tumor initiation and proliferation, or in some cases as a tumor suppressor through inhibiting proliferation and invasion. The aim of this review is to discuss miR-205 roles in different types of cancers. Given the critical effects of deregulated miR-205 on processes involved in tumorigenesis, they hold potential as novel therapeutic targets and biomarkers.
    Full-text · Article · Jan 2014 · Asian Pacific journal of cancer prevention: APJCP
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