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

Oncogene volume 29, pages 128–138 (2010)Cite this article

Abstract

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.

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Acknowledgements

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.

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Author notes

  1. Q Wang and Z -X Sun: These authors contributed equally to this work.

Authors and Affiliations

  1. Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY, USA

    Q Wang & H -S Yang

  2. Department of Pharmaceutics, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, People's Republic of China

    Z -X Sun

  3. Department of Experimental Surgery and Molecular Oncology of Solid Tumors, Medical Faculty Mannheim, University of Heidelberg, and KDFZ Heidelberg, Mannheim, Germany

    H Allgayer

  4. Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA

    H -S Yang

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  1. Q Wang
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Correspondence to H -S Yang.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Wang, Q., Sun, ZX., Allgayer, H. et al. Downregulation of E-cadherin is an essential event in activating β-catenin/Tcf-dependent transcription and expression of its target genes in Pdcd4 knockdown cells. Oncogene 29, 128–138 (2010). https://doi.org/10.1038/onc.2009.302

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