High motility of triple-negative breast cancer cells is due to repression of plakoglobin gene by metastasis modulator protein SLUG.
ABSTRACT One of highly pathogenic breast cancer cell types are the triple negative (negative in the expression of estrogen, progesterone, and ERBB2 receptors) breast cancer cells. These cells are highly motile and metastatic and are characterized by high levels of the metastasis regulator protein SLUG. Using isogenic breast cancer cell systems we have shown here that high motility of these cells is directly correlated with the levels of the SLUG in these cells. Because epithelial/mesenchymal cell motility is known to be negatively regulated by the catenin protein plakoglobin, we postulated that the transcriptional repressor protein SLUG increases the motility of the aggressive breast cancer cells through the knockdown of the transcription of the plakoglobin gene. We found that SLUG inhibits the expression of plakoglobin gene directly in these cells. Overexpression of SLUG in the SLUG-deficient cancer cells significantly decreased the levels of mRNA and protein of plakoglobin. On the contrary, knockdown of SLUG in SLUG-high cancer cells elevated the levels of plakoglobin. Blocking of SLUG function with a double-stranded DNA decoy that competes with the E2-box binding of SLUG also increased the levels of plakoglobin mRNA, protein, and promoter activity in the SLUG-high triple negative breast cancer cells. Overexpression of SLUG in the SLUG-deficient cells elevated the motility of these cells. Knockdown of plakoglobin in these low motility non-invasive breast cancer cells rearranged the actin filaments and increased the motility of these cells. Forced expression of plakoglobin in SLUG-high cells had the reverse effects on cellular motility. This study thus implicates SLUG-induced repression of plakoglobin as a motility determinant in highly disseminating breast cancer.
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ABSTRACT: Armadillo (Arm) repeat proteins contain tandem copies of a degenerate protein sequence motif that forms a conserved three-dimensional structure. Animal Arm repeat proteins function in various processes, including intracellular signalling and cytoskeletal regulation. A subset of these proteins are conserved across eukaryotic kingdoms, and non-metazoa such as Dictyostelium and Chlamydomonas possess homologues of members of the animal Arm repeat family. Higher plants also possess Arm repeat proteins, which, like their animal counterparts, function in intracellular signalling. Notably, these plant Arm proteins have novel functions. In addition, genome sequencing has identified a plethora of Arm-related proteins in Arabidopsis.Trends in Cell Biology 10/2003; 13(9):463-71. · 11.72 Impact Factor
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ABSTRACT: Epithelial-to-mesenchymal transition (EMT) is a process that plays essential roles in development and wound healing that is characterized by loss of homotypic adhesion and cell polarity and increased invasion and migration. At the molecular level, EMT is characterized by loss of E-cadherin and increased expression of several transcriptional repressors of E-cadherin expression (Zeb-1, Zeb-2, Twist, Snail, and Slug). Early work established that loss of E-cadherin and increased expression of MMP-9 was associated with a poor clinical outcome in patients with urothelial tumors, suggesting that EMT might also be associated with bladder cancer progression and metastasis. More recently, we have used global gene expression profiling to characterize the molecular heterogeneity in human urothelial cancer cell lines (n = 20) and primary patient tumors, and unsupervised clustering analyses revealed that the cells naturally segregate into two discrete "epithelial" and "mesenchymal" subsets, the latter consisting entirely of muscle-invasive tumors. Importantly, sensitivity to inhibitors of the epidermal growth factor receptor (EGFR) or type-3 fibroblast growth factor receptor (FGFR3) was confined to the "epithelial" subset, and sensitivity to EGFR inhibitors could be reestablished by micro-RNA-mediated molecular reversal of EMT. The results suggest that EMT coordinately regulates drug resistance and muscle invasion/metastasis in urothelial cancer and is a dominant feature of overall cancer biology.CANCER AND METASTASIS REVIEW 12/2009; 28(3-4):335-44. · 9.35 Impact Factor
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ABSTRACT: C-terminal binding protein family members function predominantly as transcriptional corepressors in association with sequence specific DNA-binding transcriptional repressors. The vertebrates have two CtBP genes while the invertebrates contain a single gene. Genetic studies indicate that the CtBP genes play pivotal roles in animal development. The vertebrate C-terminal binding proteins (CtBP1 and CtBP2) are highly related and are functionally redundant for certain developmental processes and non-redundant for others. The animal C-terminal binding proteins exhibit structural and functional similarity to d-isomer-specific 2-hydroxy acid dehydrogenases (D2-HDH). They function as dimers, recruiting transcriptional regulators through two protein-binding interfaces in each monomer. The corepressor complex of CtBP1 contains enzymatic constituents that mediate coordinated histone modification by deacetylation and methylation of histone H3-Lysine 9 and demethylation of histone H3-Lysine 4. CtBP also recruits the small ubiquitin-related modifier (SUMO) conjugating E2 enzyme UBC9 and a SUMO E3 ligase (HPC2), suggesting that CtBP-mediated transcriptional regulation may also involve SUMOylation of transcription factors. In addition to gene-specific transcriptional repression, CtBP1 appears to antagonize the activity of the global transcriptional coactivators, p300/CBP. Genetic evidence also suggests that the fly CtBP (dCtBP) and the vertebrate CtBP2 might activate transcription in a context-dependent manner. The transcriptional regulatory activity of CtBP is modulated by the nuclear NADH/NAD+ ratio and hence appears to be influenced by the metabolic status of the cell. The nuclear dinucleotide ratio may differentially influence the repression activities of factors that recruit CtBP through PLDLS-like motifs and those through non-PLDLS-motifs.The International Journal of Biochemistry & Cell Biology 02/2007; 39(9):1593-607. · 4.15 Impact Factor