Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex

Peinado, Héctor; Ballestar, Esteban; Esteller, Manel; Cano, Amparo

doi:10.1128/mcb.24.1.306-319.2004

Cited by 667 publications

(636 citation statements)

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“…Therefore, it is not difficult to understand why siSnail, but not siYY1 dissociated EZH2 and HDAC1/2 from the YY1 region of Ecadherin promoter. As a result of our collective present data, together with other group's findings (van der Vlag and Otte, 1999;Peinado et al, 2004;Herranz et al, 2008;von Burstin et al, 2009), herein we propose a main co-repressor complex, that is, EZH2/HDAC1/2/Snail, in the regulation of E-cadherin in NPC cells, and probably in a number of other types of human cancers. A schematic representation of the major molecular mechanisms of this complex, in NPC cells, is suggested and provided in Figure 5d.…”

Section: Ezh2 Promotes Npc Cell Aggressiveness Z-t Tong Et Alsupporting

confidence: 84%

“…Additionally, we observed that in NPC cells, the repressive function of EZH2 toward the E-cadherin was dependent on HDAC activity. Other groups previously reported that Snail mediates E-cadherin repression by the recruitment of the Sin3A/ HDAC1/2 complex (Peinado et al, 2004), and E-cadherin is suppressed by a Snail/HDAC1/HDAC2 complex to regulate metastasis of pancreatic cancer in vivo (von Burstin et al, 2009). These results, taken together, prompted us to ask (1) whether or not EZH2, the core member of PRC2, acts as a co-repressor complex with HDAC1/2 and Snail to repress E-cadherin in NPC cells, and (2) if so, in which fashion does these components interact each other.…”

Section: Ezh2 Promotes Npc Cell Aggressiveness Z-t Tong Et Almentioning

confidence: 98%

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EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin

et al. 2011

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The enhancer of zeste homolog 2 (EZH2) is upregulated and has an oncogenic role in several types of human cancer. However, the abnormalities of EZH2 and its underlying mechanisms in the pathogenesis of nasopharyngeal carcinoma (NPC) remain unknown. In this study, we found that high expression of EZH2 in NPC was associated closely with an aggressive and/or poor prognostic phenotype (Po0.05). In NPC cell lines, knockdown of EZH2 by short hairpin RNA was sufficient to inhibit cell invasiveness/metastasis both in vitro and in vivo, whereas ectopic overexpression of EZH2 supported NPC cell invasive capacity with a decreased expression of E-cadherin. In addition, ablation of endogenous Snail in NPC cells virtually totally prevented the repressive activity of EZH2 to E-cadherin, indicating that Snail might be a predominant mediator of EZH2 to suppress E-cadherin. Furthermore, co-immunoprecipitation (IP), chromatin IP and luciferase reporter assays demonstrated that in NPC cells, (1) EZH2 interacted with HDAC1/HDAC2 and Snail to form a repressive complex; (2) these components interact in a linear fashion, not in a triangular fashion, that is, HDAC1 or HDAC2 bridge the interaction between EZH2 and Snail; and (3) the EZH2/HDAC1/2/Snail complex could closely bind to the E-cadherin promoter by Snail, but not YY1, to repress E-cadherin. The data provided in this report suggest a critical role of EZH2 in the control of cell invasion and/or metastasis by forming a co-repressor complex with HDAC1/HDAC2/Snail to repress E-cadherin, an activity that might be responsible, at least in part, for the development and/or progression of human NPCs.

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Section: Ezh2 Promotes Npc Cell Aggressiveness Z-t Tong Et Alsupporting

confidence: 84%

Section: Ezh2 Promotes Npc Cell Aggressiveness Z-t Tong Et Almentioning

confidence: 98%

EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin

et al. 2011

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“…The best known factor regulating EMT is Snail; hence, great effort has been focused on describing the signaling and transduction pathways that regulate its activity. It has been reported that Snail regulates the cdh-1 locus when it is associated with SIN3A, HDAC1, and HDAC2 [63].…”

Section: The Epithelium To Mesenchymal Transitionmentioning

confidence: 99%

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Martinez-Ramirez

Dı́az-Muñoz

Butanda-Ochoa

et al. 2016

Purinergic Signalling

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The epithelium-mesenchymal transition (EMT) is an important process of cell plasticity, consisting in the loss of epithelial identity and the gain of mesenchymal characteristics through the coordinated activity of a highly regulated informational program. Although it was originally described in the embryonic development, an important body of information supports its role in pathology, mainly in cancerous and fibrotic processes. The purinergic system of inter-cellular communication, mainly based in ATP and adenosine acting throughout their specific receptors, has emerged as a potent regulator of the EMT in several pathological entities. In this context, cellular signaling associated to purines is opening the understanding of a new element in the complex regulatory network of this phenotypical differentiation process. In this review, we have summarized recent information about the role of ATP and adenosine in EMT, as a growing field with high therapeutic potential.Keywords P2 receptors . P1 receptors . Purinergic signaling . Cell migration . EMTThe purinergic system of intercellular communication General aspects The term purine (from: pure urine) was created more than 130 years ago by Emil Fischer after detailed analytical characterization of the uric acid molecule [1]. Purine molecular structure is the result of fusing pyrimidine and imidazole rings, and it exists as four N-H tautomeric forms [2]. Tautomerism of purine bases in DNA is one of the earliest reasons for mutations [3][4][5]. The interconversion of the different adenine or guanine tautomers produced mispairing with pyrimidines (which also show tautomeric forms) that may lead to changes in DNA sequence [6].Purine molecules appeared very early in the history of our planet, in the period known as Borganic evolution^, before the establishment of living systems. It has been postulated that purines could be formed by a eutectic (denoting a mixture of substances in fixed proportions that melts and freezes at a single temperature that is lower than the melting points of any of the separate constituents) concentration of HCN at extremely low temperature over a period of dozens of years [7]. Purine molecules, such as adenine and guanine, are components of the genetic material (DNA and RNA) of all living beings. Purine and pyrimidine tautomeric equilibria in nucleic acids was postulated to be significant in events such as DNA replication and repair as well as in the occurrence of point mutations [8].As nucleosides and nucleotides, purines play other highly strategic roles, acting as energy intermediates, allosteric regulators of key metabolic activities, redox molecules, and chemical messengers for signal transduction events. The two most important purines serving as extracellular ligands for paracrine and autocrine signaling are ATP and its dephosphorylated form, adenosine (ADO). ATP and ADO act as intracellular intermediate metabolites, and their presence in the

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“…Both TGF-b1-stimulated parental PANC-1 cells and (unstimulated) PANC-1-ALK5-TD clones displayed a reduced expression of epithelial markers, such as E-cadherin ( Figure 5b) and cytokeratin 18 (not shown), and a concomitant increase in mesenchymal markers N-cadherin and vimentin. Expression of the EMT-associated transcription factor Snail, which is a transcriptional repressor of E-cadherin (Peinado et al, 2004), was elevated in ALK5-TD pools, albeit moderately, likely reflecting induction in some clones but not in others (Figure 5b). Of note, the kinase-active RImL45 mutant was unable to induce these changes (Figure 5b).…”

Section: Tgf-b Receptor Type I In Tgf-b-induced Tumor Suppressionmentioning

confidence: 99%

Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

Schniewind¹,

Groth²,

Müerköster³

et al. 2007

Oncogene

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In the present study, we have analysed the effects of transforming growth factor-beta (TGF-b) signaling on the growth behavior of pancreatic carcinoma cells in vitro and on their tumorigenicity in vivo. Ectopic expression of dominant-negative mutants of the TGF-b type II receptor or type I receptor/activin receptor-like kinase 5 (ALK5) in TGF-b-sensitive pancreatic ductal adenocarcinoma PANC-1 cells prevented the TGF-b-induced activation of transfected Smad-responsive reporter genes and growth arrest. The growth-inhibitory effect was mimicked by stable expression of kinase-active ALK5 (ALK5-T204D), and was dependent on ALK5's ability to activate Smad signaling, as a ALK5-derived mutant with an intact kinase domain but deficient in its ability to activate Smads (RImL45) failed to suppress proliferation in the absence of added TGF-b. Moreover, this mutant often displayed opposite effects to those of ALK5-TD and blocked various ligand-induced responses in vitro, indicating that it acts in a dominant-negative fashion to inhibit endogenous wild-type receptors. ALK5-TD-, but not RImL45-TDtransduced cells underwent epithelial-to-mesenchymal transition, exhibited a higher ratio of thrombospondin-1 to vascular endothelial growth factor-A expression and upregulated various metastasis-associated genes. Upon orthotopic transplantation of PANC-1 clones into immunodeficient mice, ALK5-TD, but not RImL45-TD, greatly reduced tumor size and induced the formation of liver metastases in otherwise non-metastatic PANC-1 cells. These results suggest a causal, dominant role for the endogenous Smad2/3 signaling pathway in the tumor suppressor and prometastatic activities of TGF-b in pancreatic tumor cells.

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Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex

Cited by 667 publications

References 57 publications

EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin

EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

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