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Downregulation of E-cadherin is an essential event in activating beta-catenin/Tcf-dependent transcription and expression of its target genes in Pdcd4 knockdown cells.

Wang Q, Sun ZX, Allgayer H, Yang HS - Oncogene (2009)

Bottom Line: In addition, Pdcd4 knockdown stimulates urokinase-type plasminogen activator receptor (u-PAR) and c-Myc expression, whereas u-PAR and c-Myc expression can be reversed by over-expressing E-cadherin in Pdcd4 knockdown cells.Using chromatin immunoprecipitation, we showed that beta-catenin/Tcf4 directly binds to the promoters of u-PAR and c-myc in Pdcd4 knockdown cells.Futhermore, knockdown of u-PAR or c-Myc inhibits invasion in Pdcd4 knockdown cells, suggesting that both u-PAR and c-Myc contribute to invasion induced by Pdcd4 knockdown.

View Article: PubMed Central - PubMed

Affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.

ABSTRACT
We reported earlier that knockdown of tumor suppressor Pdcd4 (programed cell death 4) downregulates E-cadherin expression and activates beta-catenin/Tcf (T-cell factor)-dependent transcription in colon tumor cells. However, the underlying mechanism of these observations remains unknown. In this study, we showed that knockdown of Pdcd4 downregulates E-cadherin expression through elevated protein level of Snail. Over-expression of Pdcd4 upregulates E-cadherin expression and inhibits beta-catenin/Tcf-dependent transcription. We then showed that knockdown of E-cadherin activates beta-catenin/Tcf-dependent transcription. Conversely, over-expression of E-cadherin in Pdcd4 knockdown cells inhibits beta-catenin/Tcf-dependent transcription. In addition, Pdcd4 knockdown stimulates urokinase-type plasminogen activator receptor (u-PAR) and c-Myc expression, whereas u-PAR and c-Myc expression can be reversed by over-expressing E-cadherin in Pdcd4 knockdown cells. Using chromatin immunoprecipitation, we showed that beta-catenin/Tcf4 directly binds to the promoters of u-PAR and c-myc in Pdcd4 knockdown cells. Futhermore, knockdown of u-PAR or c-Myc inhibits invasion in Pdcd4 knockdown cells, suggesting that both u-PAR and c-Myc contribute to invasion induced by Pdcd4 knockdown. Taken together, our data showed that elevated Snail expression by Pdcd4 knockdown leads to downregulation of E-cadherin resulting in activating beta-catenin/Tcf-dependent transcription and stimulating the expression of c-Myc and u-PAR, thus providing molecular explanation of how Pdcd4 suppresses tumor invasion.

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A model depicting the pathway involved in invasion promotion caused by Pdcd4 knock-down. See text for details. E: E-cadherin; β: β-catenin.
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Figure 7: A model depicting the pathway involved in invasion promotion caused by Pdcd4 knock-down. See text for details. E: E-cadherin; β: β-catenin.

Mentions: Our previous study showed that Pdcd4 knock-down activates β-catenin/Tcf dependent transcription and promotes invasions in colon tumor cells (Wang et al., 2008). In this study, we demonstrated that Pdcd4 knock-down up-regulates Snail resulting in down-regulation of E-cadherin expression. In addition, we showed that down-regulation of E-cadherin is a key event for activating β-catenin/Tcf dependent transcription. Activation of β-catenin/Tcf dependent transcription subsequently leads to the expression of invasion promoting genes, u-PAR and c-myc. Thus, our previous (Wang et al., 2008) and present studies collectively reveal the mechanism by which Pdcd4 knock-down promotes invasion in colon tumor cells. Our model shows that (1) Pdcd4 knock-down leads to down-regulation of E-cadherin through up-regulating Snail expression, (2) decreased E-cadherin expression changes cell morphology and releases β-catenin, and (3) the free β-catenin then translocates into the nucleus, binds to Tcf4 transcription factors, and activates β-catenin/Tcf dependent transcription to stimulate the expression of u-PAR and c-Myc, which promote tumor cell invasion (Figure 7).


Downregulation of E-cadherin is an essential event in activating beta-catenin/Tcf-dependent transcription and expression of its target genes in Pdcd4 knockdown cells.

Wang Q, Sun ZX, Allgayer H, Yang HS - Oncogene (2009)

A model depicting the pathway involved in invasion promotion caused by Pdcd4 knock-down. See text for details. E: E-cadherin; β: β-catenin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2920641&req=5

Figure 7: A model depicting the pathway involved in invasion promotion caused by Pdcd4 knock-down. See text for details. E: E-cadherin; β: β-catenin.
Mentions: Our previous study showed that Pdcd4 knock-down activates β-catenin/Tcf dependent transcription and promotes invasions in colon tumor cells (Wang et al., 2008). In this study, we demonstrated that Pdcd4 knock-down up-regulates Snail resulting in down-regulation of E-cadherin expression. In addition, we showed that down-regulation of E-cadherin is a key event for activating β-catenin/Tcf dependent transcription. Activation of β-catenin/Tcf dependent transcription subsequently leads to the expression of invasion promoting genes, u-PAR and c-myc. Thus, our previous (Wang et al., 2008) and present studies collectively reveal the mechanism by which Pdcd4 knock-down promotes invasion in colon tumor cells. Our model shows that (1) Pdcd4 knock-down leads to down-regulation of E-cadherin through up-regulating Snail expression, (2) decreased E-cadherin expression changes cell morphology and releases β-catenin, and (3) the free β-catenin then translocates into the nucleus, binds to Tcf4 transcription factors, and activates β-catenin/Tcf dependent transcription to stimulate the expression of u-PAR and c-Myc, which promote tumor cell invasion (Figure 7).

Bottom Line: In addition, Pdcd4 knockdown stimulates urokinase-type plasminogen activator receptor (u-PAR) and c-Myc expression, whereas u-PAR and c-Myc expression can be reversed by over-expressing E-cadherin in Pdcd4 knockdown cells.Using chromatin immunoprecipitation, we showed that beta-catenin/Tcf4 directly binds to the promoters of u-PAR and c-myc in Pdcd4 knockdown cells.Futhermore, knockdown of u-PAR or c-Myc inhibits invasion in Pdcd4 knockdown cells, suggesting that both u-PAR and c-Myc contribute to invasion induced by Pdcd4 knockdown.

View Article: PubMed Central - PubMed

Affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.

ABSTRACT
We reported earlier that knockdown of tumor suppressor Pdcd4 (programed cell death 4) downregulates E-cadherin expression and activates beta-catenin/Tcf (T-cell factor)-dependent transcription in colon tumor cells. However, the underlying mechanism of these observations remains unknown. In this study, we showed that knockdown of Pdcd4 downregulates E-cadherin expression through elevated protein level of Snail. Over-expression of Pdcd4 upregulates E-cadherin expression and inhibits beta-catenin/Tcf-dependent transcription. We then showed that knockdown of E-cadherin activates beta-catenin/Tcf-dependent transcription. Conversely, over-expression of E-cadherin in Pdcd4 knockdown cells inhibits beta-catenin/Tcf-dependent transcription. In addition, Pdcd4 knockdown stimulates urokinase-type plasminogen activator receptor (u-PAR) and c-Myc expression, whereas u-PAR and c-Myc expression can be reversed by over-expressing E-cadherin in Pdcd4 knockdown cells. Using chromatin immunoprecipitation, we showed that beta-catenin/Tcf4 directly binds to the promoters of u-PAR and c-myc in Pdcd4 knockdown cells. Futhermore, knockdown of u-PAR or c-Myc inhibits invasion in Pdcd4 knockdown cells, suggesting that both u-PAR and c-Myc contribute to invasion induced by Pdcd4 knockdown. Taken together, our data showed that elevated Snail expression by Pdcd4 knockdown leads to downregulation of E-cadherin resulting in activating beta-catenin/Tcf-dependent transcription and stimulating the expression of c-Myc and u-PAR, thus providing molecular explanation of how Pdcd4 suppresses tumor invasion.

Show MeSH
Related in: MedlinePlus