We reported earlier that knockdown of tumor suppressor Pdcd4 (programed cell death 4) downregulates E-cadherin expression and activates Β-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 Β-catenin/Tcf-dependent transcription. We then showed that knockdown of E-cadherin activates Β-catenin/Tcf-dependent transcription. Conversely, over-expression of E-cadherin in Pdcd4 knockdown cells inhibits Β-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 Β-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 Β-catenin/Tcf-dependent transcription and stimulating the expression of c-Myc and u-PAR, thus providing molecular explanation of how Pdcd4 suppresses tumor invasion.
|Number of pages||11|
|State||Published - Jan 2010|
Bibliographical noteFunding Information:
We thank Dr Ji Hshiung Chen (Tzu Chi University, Taiwan) for kindly providing E-cadherin promoter and Dr Xiaoling Guo for technical support. This work was supported by NCI Grant R01CA129015, ACS Institutional Research Grant IRG-85-001-19, and NCRR CORBE pilot grant P20RR020171.
- B-catenin/Tcf-dependent transcription
- Stably knockdown
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research