TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer

Department of Molecular Carcinogenesis, The Bob Champion Prostate Stem Cell Team, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
British Journal of Cancer (Impact Factor: 4.84). 12/2008; 99(11):1849-58. DOI: 10.1038/sj.bjc.6604774
Source: PubMed


Prostate cancer is the most frequently diagnosed male cancer, and its clinical outcome is difficult to predict. The disease may involve the inappropriate expression of genes that normally control the proliferation of epithelial cells in the basal layer and their differentiation into luminal cells. Our aim was to identify novel basal cell markers and assess their prognostic and functional significance in prostate cancer. RNA from basal and luminal cells isolated from benign tissue by immunoguided laser-capture microdissection was subjected to expression profiling. We identified 112 and 267 genes defining basal and luminal populations, respectively. The transcription factor TEAD1 and the ubiquitin ligase c-Cbl were identified as novel basal cell markers. Knockdown of either marker using siRNA in prostate cell lines led to decreased cell growth in PC3 and disrupted acinar formation in a 3D culture system of RWPE1. Analyses of prostate cancer tissue microarray staining established that increased protein levels of either marker were associated with decreased patient survival independent of other clinicopathological metrics. These data are consistent with basal features impacting on the development and clinical course of prostate cancers.

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    • "Elevated serum chromogranin A levels are indicative of poor prognosis and decreased survival [20]. Other differentially expressed molecules with prognostic potential include the urokinase plasminogen activation (uPA) [21], TGF-í µí»½1 [22] [23], MUC1 [24], CD24 [25], hCAP-D3 [26], vesicular monoamine transporter 2 (SLC18A2) [27], TEA domain family member 1 (TEAD1), c-Cbl [28], SOX7 and SOX9 [29], nuclear receptor binding protein 1 (NRBP1) [30], CD147 [31], and Wnt5a [32]. Each of these markers will require proper validation to ensure their clinical utility. "
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    ABSTRACT: The discovery of prostate cancer biomarkers has been boosted by the advent of next-generation sequencing (NGS) technologies. Nevertheless, many challenges still exist in exploiting the flood of sequence data and translating them into routine diagnostics and prognosis of prostate cancer. Here we review the recent developments in prostate cancer biomarkers by high throughput sequencing technologies. We highlight some fundamental issues of translational bioinformatics and the potential use of cloud computing in NGS data processing for the improvement of prostate cancer treatment.
    07/2013; 2013:901578. DOI:10.1155/2013/901578
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    • "Although the regulation of TEAD1 transcription is poorly understood so far, its expression is misregulated in several types of cancers. TEAD1 has been found either upregulated, for instance in prostatic or pancreatic cancers [33], [34], or conversely decreased in bladder or breast cancer, for example (as reported by the ONCOMINE database [35], [36], [37]). Nevertheless the functional outcome and significance of such TEAD1 modulations, as well as its bona fide target genes relevant to tumorigenesis remained elusive. "
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    ABSTRACT: Background TEA domain (TEAD) proteins are highly conserved transcription factors involved in embryonic development and differentiation of various tissues. More recently, emerging evidences for a contribution of these proteins towards apoptosis and cell proliferation regulation have also been proposed. These effects appear to be mediated by the interaction between TEAD and its co-activator Yes-Associated Protein (YAP), the downstream effector of the Hippo tumour suppressor pathway. Methodology/Principal Findings We further investigated the mechanisms underlying TEAD-mediated apoptosis regulation and showed that overexpression or RNAi-mediated silencing of the TEAD1 protein is sufficient to protect mammalian cell lines from induced apoptosis, suggesting a proapoptotic function for TEAD1 and a non physiological cytoprotective effect for overexpressed TEAD1. Moreover we show that the apoptotic resistance conferred by altered TEAD1 expression is mediated by the transcriptional up-regulation of Livin, a member of the Inhibitor of Apoptosis Protein (IAP) family. In addition, we show that overexpression of a repressive form of TEAD1 can induce Livin up-regulation, indicating that the effect of TEAD1 on Livin expression is indirect and favoring a model in which TEAD1 activates a repressor of Livin by interacting with a limiting cofactor that gets titrated upon TEAD1 up-regulation. Interestingly, we show that overexpression of a mutated form of TEAD1 (Y421H) implicated in Sveinsson's chorioretinal atrophy that strongly reduces its interaction with YAP as well as its activation, can induce Livin expression and protect cells from induced apoptosis, suggesting that YAP is not the cofactor involved in this process. Conclusions/Significance Taken together our data reveal a new, Livin-dependent, apoptotic role for TEAD1 in mammals and provide mechanistic insight downstream of TEAD1 deregulation in cancers.
    PLoS ONE 09/2012; 7(9). DOI:10.1371/journal.pone.0045498 · 3.23 Impact Factor
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    • "To test for potential association with functional genes, we used the online software blast (Altschul et al. 1990) to investigate similarities between the microsatellite flanking sequences of Lid 8 and Rru 4 and the genome library of zebra fish (Danio rerio, a cyprinid fish biological model). We found that Rru 4 was inserted within a gene sequence coding for transcriptional enhancer factor (TEA) domain family member 1. TEA domain proteins are transcriptional factors that might be implicated in the regulation of cell proliferation (Knight et al. 2008) as well as in the immune response against viral and parasitic infections (Cuddapah, Cui & Zhao 2008). In the case of Lid 8, we found no evidence for a link between a coding gene and Lid 8 microsatellite flanking regions. "
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