E-Cadherin Regulates Metastasis of Pancreatic Cancer In Vivo and Is Suppressed by a SNAIL/HDAC1/HDAC2 Repressor Complex

Burstin, Johannes von; Eser, Stefan; Paul, Mariel C.; Seidler, Barbara; Brandl, Martina; Messer, Marlena; Werder, Alexander von; Schmidt, Annegret; Mages, Jörg; Pagel, Philipp; Schnieke, Angelika; Schmid, Roland M.; Schneider, Günter; Saur, Dieter

doi:10.1053/j.gastro.2009.04.004

Cited by 320 publications

(296 citation statements)

References 45 publications

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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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“…28,29 Snail transcriptionally represses E-cadherin by recruiting histone deacetylases (HDAC) to the E-boxes of the E-cadherin promoter. 30 Interestingly, Yin et al showed that Snail overexpression correlated with lymph node invasion and distant metastasis in human pancreatic cancer. 31 Also, Snail overexpression in Panc-1 tumors.…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 promotes pancreatic cancer cell differentiation and restores membranous E-cadherin via suppression of the epithelial-mesenchymal transition

et al. 2011

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“…28 Recently it has been shown that the silencing of E-cadherin expression in highly metastatic cells is mediated by a transcriptional repressor complex containing Snail and histone deacetylases 1 and 2. 29 Although E-cadherin has been prominently studied for its role in tumorigenesis, evidencing that the loss of E-cadherin is a critical initiation step in the epithelial-to-mesenchymal transition associated with the invasiveness of tumors, metastatic dissemination and a poor prognosis for several different types of tumor, 30 there are increasing reports of its contribution to the effectiveness of antitumoral therapies. 17,19,20,31 Moreover, E-cadherin has been proposed as a biomarker for therapies, such as EGFR tyrosine kinase activity inhibitors or other molecules interfering with EGFR signaling.…”

Section: Discussionmentioning

confidence: 99%

E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models

et al. 2010

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The thymidine kinase/ganciclovir (TK/GCV) cancer gene therapy approach is based on inducing GCV metabolite cytotoxicity in tumor cells expressing the herpes simplex virus TK gene and exposed to GCV. A bystander effect, mediated by gap junctions, accounts for the transfer of toxic metabolites from TK-expressing cells to neighboring cells. It has been proposed that E-cadherin participates in the formation and function of such gap junctions. In this study we investigate the influence of E-cadherin on TK/GCV suicide therapy with a panel of cellular and in vivo models of pancreatic ductal adenocarcinoma. We observed a strong correlation of E-cadherin expression and the TK/GCV bystander effect, associated with the modulation of gap junction communication and connexin expression or localization. Importantly, the co-expression of TK and E-cadherin genes in the adenoviral vector AdTat8TKIE improved TK/GCV cytotoxicity and triggered a potent antitumoral effect, superior to standard AdTat8TK/GCV in MIAPaCa-2 xenografts. The increased expression of E-cadherin resulted in the reduction of the bcl-2 content. Interestingly, the knockdown of bcl-2 sensitized cells to TK/GCV. Thus, we propose that by restoring E-cadherin in pancreatic tumor cells we will improve TK/GCV therapy, both by enhancing the bystander effect and by facilitating the induction of apoptosis.

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E-Cadherin Regulates Metastasis of Pancreatic Cancer In Vivo and Is Suppressed by a SNAIL/HDAC1/HDAC2 Repressor Complex

Cited by 320 publications

References 45 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

Caveolin-1 promotes pancreatic cancer cell differentiation and restores membranous E-cadherin via suppression of the epithelial-mesenchymal transition

E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models

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