Function of the zinc-finger transcription factor SNAI2 in cancer and development.
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.
- SourceAvailable from: Nicolo Riggi[Show abstract] [Hide abstract]
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.
- [Show abstract] [Hide abstract]
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
- [Show abstract] [Hide abstract]
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.