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

Q. Wang, Z. X. Sun, H. Allgayer, H. S. Yang

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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.

Original languageEnglish
Pages (from-to)128-138
Number of pages11
JournalOncogene
Volume29
Issue number1
DOIs
StatePublished - Jan 2010

Bibliographical note

Funding 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.

Keywords

  • B-catenin/Tcf-dependent transcription
  • C-Myc
  • E-cadherin
  • Pdcd4
  • Stably knockdown
  • U-PAR

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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