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Sanchez-Tillo E.,Group of Transcriptional Regulation of Gene Expression | Sanchez-Tillo E.,CIBER ISCIII | De Barrios O.,Group of Transcriptional Regulation of Gene Expression | Siles L.,Group of Transcriptional Regulation of Gene Expression | And 9 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Carcinoma cells enhance their invasive capacity through dedifferentiation and dissolution of intercellular adhesions. A key activator of this process is the ZEB1 transcription factor, which is induced in invading cancer cells by canonical Wnt signaling (β-catenin/TCF4). Tumor invasiveness also entails proteolytic remodeling of the peritumoral stroma. This study aimed to investigate the potential regulation by ZEB1 of the plasminogen proteolytic system constituted by the urokinase plasminogen activator (uPA), and its inhibitor, plasminogen activator inhibitor-1 (PAI-1). Experimental Design: Through multiple experimental approaches, colorectal carcinoma (CRC) cell lines and samples from human primary CRC and ZEB1 (-/-) mice were used to examine ZEB1-mediated regulation of uPA and PAI-1 at the protein, mRNA, and transcriptional level. Results: ZEB1 regulates uPA and PAI-1 in opposite directions: induces uPA and inhibits PAI-1. In vivo expression of uPA depends on ZEB1 as it is severely reduced in the developing intestine of ZEB1 null (-/-) mice. Optimal induction of uPA by Wnt signaling requires ZEB1 expression. ZEB1 binds to the uPA promoter and activates its transcription through a mechanism implicating the histone acetyltransferase p300. In contrast, inhibition of PAI-1 by ZEB1 does not involve transcriptional repression but rather downregulation of mRNA stability. ZEB1-mediated tumor cell migration and invasion depend on its induction of uPA. ZEB1 coexpresses with uPA in cancer cells at the invasive front of CRCs. Conclusions: ZEB1 promotes tumor invasiveness not only via induction in cancer cells of a motile dedifferentiated phenotype but also by differential regulation of genes involved in stroma remodelling. © 2012 American Association for Cancer Research. Source


Siles L.,Group of Transcriptional Regulation of Gene Expression | Sanchez-Tillo E.,Group of Transcriptional Regulation of Gene Expression | Lim J.-W.,University of Washington | Darling D.S.,University of Louisville | And 4 more authors.
Molecular and Cellular Biology | Year: 2013

Skeletal muscle development is orchestrated by the myogenic regulatory factor MyoD, whose activity is blocked in myoblasts by proteins preventing its nuclear translocation and/or binding to G/C-centered E-boxes in target genes. Recent evidence indicates that muscle gene expression is also regulated at the cis level by differential affinity for DNA between MyoD and other E-box binding proteins during myogenesis. MyoD binds to G/C-centered E-boxes, enriched in muscle differentiation genes, in myotubes but not in myoblasts. Here, we used cell-based and in vivo Drosophila, Xenopus laevis, and mouse models to show that ZEB1, a G/C-centered E-box binding transcriptional repressor, imposes a temporary stage-dependent inhibition of muscle gene expression and differentiation via CtBP-mediated transcriptional repression. We found that, contrary to MyoD, ZEB1 binds to G/C-centered E-boxes in muscle differentiation genes at the myoblast stage but not in myotubes. Its knockdown results in precocious expression of muscle differentiation genes and acceleration of myotube formation. Inhibition of muscle genes by ZEB1 occurs via transcriptional repression and involves recruitment of the CtBP corepressor. Lastly, we show that the pattern of gene expression associated with muscle differentiation is accelerated in ZEB1-/- mouse embryos. These results set ZEB1 as an important regulator of the temporal pattern of gene expression controlling muscle differentiation ©2013, American Society for Microbiology. Source


Sanchez-Tillo E.,Group of Transcriptional Regulation of Gene Expression | Fanlo L.,Group of Transcriptional Regulation of Gene Expression | Fanlo L.,University Pompeu Fabra | Siles L.,Group of Transcriptional Regulation of Gene Expression | And 13 more authors.
Cell Death and Differentiation | Year: 2014

Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a poor response to treatment and prognosis. Constitutive activation of different signaling pathways in subsets of MCLs, through genetic and/or nongenetic alterations, endows tumor cells with enhanced proliferation and reduced apoptosis. The canonical Wnt pathway (β-catenin/TCF-LEF), implicated in the pathogenesis of numerous cancers, is constitutively active in half of MCLs. Here, we show that ZEB1, a transcription factor better known for promoting metastasis in carcinomas, is expressed in primary MCLs with active Wnt signaling. ZEB1 expression in MCL cells depends on Wnt, being downregulated by β-catenin knockdown or blocking of Wnt signaling by salinomycin. Knockdown of ZEB1 reduces in vitro cell viability and proliferation in MCL cells, and, importantly, tumor growth in mouse xenograft models. ZEB1 activates proliferation-associated (HMGB2, UHRF1, CENPF, MYC, MKI67, and CCND1) and anti-apoptotic (MCL1, BCL2, and BIRC5) genes and inhibits pro-apoptotic ones (TP53, BBC3, PMAIP1, and BAX). We show that ZEB1 expression in MCL cells determines differential resistance to chemotherapy drugs and regulates transporters involved in drug influx/efflux. Downregulation of ZEB1 by salinomycin increases the sensitivity of MCL cells to the cytotoxic effect of doxorubicin, cytarabine and gemcitabine. Lastly, salinomycin and doxorubicin display a synergistic effect in established and primary MCL cells. These results identify ZEB1 in MCL where it promotes cell proliferation, enhanced tumor growth and a differential response to chemotherapy drugs. ZEB1 could thus potentially become a predictive biomarker and therapeutic target in this lymphoma. © 2014 Macmillan Publishers Limited. Source


Sanchez-Tillo E.,Group of Transcriptional Regulation of Gene Expression | Sanchez-Tillo E.,CIBER ISCIII | Liu Y.,James Graham Brown Cancer Center | Liu Y.,Louisville Health Science Center | And 14 more authors.
Cellular and Molecular Life Sciences | Year: 2012

Cancer is a complex multistep process involving genetic and epigenetic changes that eventually result in the activation of oncogenic pathways and/or inactivation of tumor suppressor signals. During cancer progression, cancer cells acquire a number of hallmarks that promote tumor growth and invasion. A crucial mechanism by which carcinoma cells enhance their invasive capacity is the dissolution of intercellular adhesions and the acquisition of a more motile mesenchymal phenotype as part of an epithelial- to-mesenchymal transition (EMT). Although many transcription factors can trigger it, the full molecular reprogramming occurring during an EMT is mainly orchestrated by three major groups of transcription factors: the ZEB, Snail and Twist families. Upregulated expression of these EMT-activating transcription factors (EMT-ATFs) promotes tumor invasiveness in cell lines and xenograft mice models and has been associated with poor clinical prognosis in human cancers. Evidence accumulated in the last few years indicates that EMT-ATFs also regulate an expanding set of cancer cell capabilities beyond tumor invasion. Thus, EMT-ATFs have been shown to cooperate in oncogenic transformation, regulate cancer cell stemness, override safeguard programs against cancer like apoptosis and senescence, determine resistance to chemotherapy and promote tumor angiogenesis. This article reviews the expanding portfolio of functions played by EMT-ATFs in cancer progression. © Springer Basel AG 2012. Source

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