Function of the zinc-finger transcription factor SNAI2 in cancer and development

Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain.
Annual Review of Genetics (Impact Factor: 18.12). 02/2007; 41:41-61. DOI: 10.1146/annurev.genet.41.110306.130146
Source: PubMed

ABSTRACT Elucidation of the molecular mechanisms that underlie disease development is still a tremendous challenge for basic science, and a prerequisite to the development of new and disease-specific targeted therapies. This review focuses on the function of SNAI2, a member of the Snail family of zinc-finger transcription factors, and discusses its possible role in disease development. SNAI2 has been implicated in diseases of melanocyte development and cancer in humans. Many malignancies arise from a rare population of cells that alone have the ability to self-renew and sustain the tumor (i.e., cancer stem cells). SNAI2 controls key aspects of stem cell function in mouse and human, suggesting that similar mechanisms control normal development and cancer stem cell properties. These insights are expected to contribute significantly to the genetics of cancer and to the development of both cancer therapy and new methods for assessing treatment efficacy.

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    • "Several of these activated targets have established roles as oncogenes in other cellular contexts. In contrast, genes directly repressed by EWS-FLI1 include the known tumor suppressors ERRFI1 (Duncan et al., 2010), CABLES1 (Arnason et al., 2013), IER3 (Sebens Mü erkö ster et al., 2008), and TGFBI (Wang et al., 2012) as well as mesenchymal lineage factors such as SNAI2 (Cobaleda et al., 2007), TRPS1 (Zhang et al., 2012), and CD73 (Chamberlain et al., 2007) (Tables S3 and S4). "
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    ABSTRACT: The aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation. Copyright © 2014 Elsevier Inc. All rights reserved.
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    • "Snail belongs to the Snail superfamily of zinc finger transcription factors [10]. Snail and Slug, a related superfamily member, are expressed in the early mesoderm and neural crest during development [11] [12] [13]. These two zinc finger transcription factors repress E-cadherin transcription through an interaction of their C-terminal region with a 5 0 -CACCTG-3 0 sequence (referred as E-box) in the cadherin promoter [14] [15]. "
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    ABSTRACT: Epithelial-mesenchymal transition (EMT), a key process in the tumor metastatic cascade, is characterized by the loss of cell-cell junctions and cell polarity as well as the acquisition of migratory and invasive properties. However, the precise molecular events that initiate this complex EMT process are poorly understood. Snail is a regulator of EMT that represses E-cadherin transcription through its interaction with proximal E-boxes in the promoter region of target genes. To investigate the role of Snail in EMT, we generated stable Snail transfectants using the oral squamous cell carcinoma cell line HSC-4 (Snail/HSC-4). Snail/HSC-4 cells had a spindle-shaped mesenchymal morphology, and enhanced migration and invasiveness relative to control cells. Consistent with these EMT changes, the downregulation of epithelial marker proteins, E-cadherin and desmoglein 2, and the upregulation of mesenchymal marker proteins, vimentin and N-cadherin were detected. Despite these observations, the mRNA levels of E-cadherin and desmoglein 2 did not decrease significantly. Although E-cadherin and desmoglein 2 proteins were stable in parental HSC-4 cells, these proteins were rapidly degraded in Snail/HSC-4 cells. The degradation of E-cadherin, but not desmoglein 2, was inhibited by dynasore, an inhibitor of dynamin-dependent endocytosis. Therefore, in HSC-4 cells Snail regulates levels of these proteins both transcriptionaly and post-translationally.
    Biochemical and Biophysical Research Communications 12/2012; 430(3). DOI:10.1016/j.bbrc.2012.12.060 · 2.28 Impact Factor
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    • "SNAI2 regulates the DCTN5 gene promoter (Fig. 5) that contains E2-box sequences (CAGGTG/CACCTG), the classical binding site of SNAI2 [13] [14] [15] [16]. We evaluated DCTN5 levels in the SNAI2 knocked down cells; we found that DCTN5 mRNA and protein levels are increased significantly in these cells (Fig. 3 and Fig. 4). "
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    ABSTRACT: We hypothesize that the transcriptional repressor protein SLUG down regulates some key components of the dynein/dynactin pathway of RTK internalization in human breast tumor cells resulting in increase in the surface levels of these receptors, thus adding to the mechanisms of malignant transformation of these cells. The specific aims of the research are (a) To evaluate the nuclear levels of SLUG in relation to the surface levels of RTKs in human breast cancer cells of different grade and pathology by tissue microarray analysis; (b) To evaluate the levels of mRNAs of the member proteins of the dynein and dynactin complexes in breast cancer cells with different levels of SLUG protein; and, (c) To evaluate whether knock down of individual SLUG-target proteins in the dynein/dynactin pathway increases the levels of RTKs on the cell surface in the SLUG-positive human breast cancer cells and thus increases the rate of proliferations of these cells.
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