SLUG: Critical regulator of epithelial cell identity in breast development and cancer

Phillips, Sarah; Kuperwasser, Charlotte

doi:10.4161/19336918.2014.972740

Cited by 116 publications

(112 citation statements)

References 115 publications

(176 reference statements)

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“…We have previously shown that Slug protein is abundantly expressed yet undergoes rapid turnover in normal mammary epithelial cells (Phillips et al, 2014; Proia et al, 2011). Indeed, in immortalized, non-transformed MCF10A human breast epithelial cells, Slug is rapidly degraded upon cycloheximide (CHX) blockade of de novo protein synthesis, exhibiting a half-life of ~80 min (Fig 1A).…”

Section: Resultsmentioning

confidence: 99%

“…To identify proteins that may contribute to the regulation of Slug protein levels, we performed immunoprecipitation of Slug followed by mass spectrometry (co-IP/MS). This proteomic approach identified 287 unique Slug-binding partners (Table S1), several of which have been previously validated (Kao et al, 2014; Phillips et al, 2014; Wu et al, 2012). We interrogated this list of Slug-binding partners for common molecular functions using the DAVID functional annotation tool (Fig 1B & Fig S1A) (http://david.niaid.nih.gov).…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have identified the transcriptional repressor SNAI2 /Slug as a critical determinant underlying these malignant phenotypes (DiMeo et al, 2009; Phillips and Kuperwasser, 2014; Proia et al, 2011; Samanta et al, 2016; Storci et al, 2008). In cancer biology, Slug is well known to promote tumor progression and metastasis through the epithelial-mesenchymal transition (EMT), causing loss of cell adhesion and polarity while conferring migratory and invasive properties (Polyak and Weinberg, 2009; Yang and Weinberg, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…In cancer biology, Slug is well known to promote tumor progression and metastasis through the epithelial-mesenchymal transition (EMT), causing loss of cell adhesion and polarity while conferring migratory and invasive properties (Polyak and Weinberg, 2009; Yang and Weinberg, 2008). In addition, studies on mammary gland biology have outlined essential roles for Slug in orchestrating transcriptional programs for stem cell self-renewal and basal mammary epithelial cell differentiation (Cobaleda et al, 2006; Guo et al, 2012; Nassour et al, 2012; Phillips et al, 2014). By suppressing the luminal differentiation program while activating EMT, high Slug expression levels bias tumor development toward stem/basal-like phenotypes and enable the adoption of tumor-initiating and invasive capabilities (DiMeo et al, 2009; Proia et al, 2011; Samanta et al, 2016; Storci et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…By suppressing the luminal differentiation program while activating EMT, high Slug expression levels bias tumor development toward stem/basal-like phenotypes and enable the adoption of tumor-initiating and invasive capabilities (DiMeo et al, 2009; Proia et al, 2011; Samanta et al, 2016; Storci et al, 2008). Experimental depletion of Slug diminishes these aggressive traits, and SNAI2 knockout animals are resistant to mammary tumorigenesis (Phillips et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

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The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer

Zhou

Wronski

et al. 2016

Cell Reports

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Summary Overabundance of Slug protein is common in human cancer and represents an important determinant underlying the aggressiveness of basal-like breast cancer (BLBC). Despite its importance, this transcription factor is rarely mutated in BLBC, and the mechanism of its deregulation in cancer remains unknown. Here we report that Slug undergoes acetylation-dependent protein degradation and identify the deacetylase SIRT2 as a key mediator of this post-translational mechanism. SIRT2 inhibition rapidly destabilizes Slug, whereas SIRT2 overexpression extends Slug stability. We show that SIRT2 deacetylates Slug protein at lysine residue K116 to prevent Slug degradation. Interestingly, SIRT2 is frequently amplified and highly expressed in BLBC. Genetic depletion and pharmacological inactivation of SIRT2 in BLBC cells reverse Slug stabilization, cause the loss of clinically relevant pathological features of BLBC, and inhibit tumor growth. Our results suggest that targeting SIRT2 may be a rational strategy for diminishing Slug abundance and its associated malignant traits in BLBC.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer

Zhou

Wronski

et al. 2016

Cell Reports

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Membrane‐tethered syntaxin‐4 locally abrogates E‐cadherin function and activates Smad signals, contributing to asymmetric mammary epithelial morphogenesis

Hirose

Shirai

Hirai

2018

J of Cellular Biochemistry

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Spatial and temporal epithelial-mesenchymal transition (EMT) is a critical event for the generation of asymmetric epithelial architectures. We found that only restricted cell populations in the morphogenic mammary epithelia extrude syntaxin-4, a plasmalemmal t-SNARE protein, and that epithelial cell clusters with artificial heterogenic presentation of extracellular syntaxin-4 undergo asymmetric morphogenesis. A previous study revealed that inducible expression of cell surface syntaxin-4 causes EMT-like cell behaviors in the clonal mammary epithelial cells, where laminin-mediated signals were abolished so that cells readily succumb to initiate EMT. The present study added new mechanistic insight into syntaxin-4-driven EMT-like cell behaviors. Extracellular syntaxin-4 directly perturbs E-cadherin-mediated epithelial cell-cell adhesion and activates Smad signals. We found that the epithelial cells activated Smad2/3 upon induction of expression of extracellular syntaxin-4, leading to the upregulation of certain transcriptional targets of these TGF-β signaling mediators. Intriguingly, however, mRNA expression of canonical EMT initiators, such as Snail and Slug, was unchanged. In addition, E-cadherin protein was steeply decreased, yet its transcriptional expression remained constant for a couple of days. We found that extracellular syntaxin-4 directly bound to E-cadherin and sequestered β-catenin from cell-cell contact sites, perturbing intercellular adhesive property. The functional ablation of E-cadherin by syntaxin-4 was further validated by L cells with stably expressing E-cadherin, in which cells shows intercellular adhesive property solely by E-cadherin. These results underline the role of local exportation of syntaxin-4 for onset of complex epithelial morphogenesis.

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Dysregulated N6‐methyladenosine methylation writer METTL3 contributes to the proliferation and migration of gastric cancer

Liu

Yang

Sui

et al. 2019

Journal Cellular Physiology

107

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Accumulating evidence implies that N6-methyladenosine (m6A) methylation participated in the tumorigenesis of gastric cancer (GC). Here we synthetically analyzing the prognostic value and expression profile of seven m6A methylation-relevant genes through silico analysis of sequencing data downloaded from The Cancer Genome Atlas, Kaplan-Meier plotter, and Gene Expression Omnibus database. We explored the methyltransferase-like 3 (METTL3) expression in GC cell line and tumor tissues by reverse transcription quantitative polymerase chain reaction and western blot analysis.The m6A methylation status of total RNA was measured by m6A RNA methylation quantification kit. Small interfering RNA was used to establish METTL3 knockdown cell lines. We also measure the proliferation and migration capability GC cell. Furthermore, we detect the epithelial cell mesenchymal transition marker and m6A methylation level after METTL3 knock down. Our result revealed that METTL3 was significantly increased in GC tissues compared with control in big crowd data sets. Survival analysis showed that METTL3 serve as a poor prognostic factor for GC patients. The expression level of METTL3 gradually increased with the progress of tumor stage and grade. GFI1 is an important transcription factor associated with METTL3. We verified the up-trend of METTL3 in messenger RNA and protein expression and observed a significant increase in the m6A methylation status of total RNA in the GC cells and tissues. METTL3 knockdown inhibited total RNA m6A methylation level, as well as cell proliferation and migration capacity. Moreover, METTL3 knockdown decreased α-smooth muscle actin.Taken together, our finding revealed that m6A methylation writer METTL3 serve as an oncogene in tumorigenesis of GC.

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SLUG: Critical regulator of epithelial cell identity in breast development and cancer

Cited by 116 publications

References 115 publications

The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer

The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer

Membrane‐tethered syntaxin‐4 locally abrogates E‐cadherin function and activates Smad signals, contributing to asymmetric mammary epithelial morphogenesis

Dysregulated N6‐methyladenosine methylation writer METTL3 contributes to the proliferation and migration of gastric cancer

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