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
Open accessAbstract
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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PDCD4 knockdown inhibits E-cadherin expression up-regulating the zinc-finger transcription factor SNAIL.
“On the other hand, PDCD4 knockdown inhibits E-cadherin expression up-regulating the zinc-finger transcription factor SNAIL [36].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [36]
Down-regulation of E-cadherin activates β-catenin/Tcf-dependent transcription, stimulating expression of C-MYC.
“The down-regulation of E-cadherin activates β-catenin/T-cell specific transcription factor (Tcf)-dependent transcription, stimulating the expression of C-MYC, one of the target gens [36].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [36]
PDCD4 knockdown upregulates C-MYC expression via the SNAIL-E-cadherin-β-catenin/Tcf-C-MYC pathway.
“Altogether, PDCD4 knockdown upregulates C-MYC expression via SNAIL-E-cadherin-β-catenin/Tcf-C-MYC pathway and in turn the C-MYC may stimulate MAP4K1 expression and activate the downstream factors JNK and AP-1.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [36]
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Research works printed but not linked: 32
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- Authors
- Wang, Q., Sun, Z. X., Allgayer, H., & Yang, H. S.
- Affiliations
- University of Kentucky (US)
- Beijing University of Chinese Medicine (CN)
- Heidelberg University (DE)
- Corresponding author
- Yang, H -S
- Venue
- Oncogene
- Published
- 2009-09-28
- Volume
- 29
- Issue
- 1
- Pages
- 128-138
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC2920641
- OpenAlex
- W2014235909
- Cited by
- 89
- References
- 37
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 11 · 2017: 5 · 2016: 6 · 2015: 2 · 2014: 7 · 2013: 7 · 2012: 4
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA129015)
- National Center for Research Resources (P20RR020171)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- PDCD4, E-cadherin, snails, transcriptional repression, urokinase-type plasminogen activator receptor, c-Myc, tumor invasion, colon cancer, tumor suppressor, transcriptional regulation
- MeSH terms
- Snail Family Transcription Factors, Humans, Mutation, Protein Binding, Transcription Factors, Transcription, Genetic, Transfection, Blotting, Western, Down-Regulation, Cadherins, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, RNA-Binding Proteins, HT29 Cells, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Cell Line, Tumor, Chromatin Immunoprecipitation, Apoptosis Regulatory Proteins, beta Catenin, TCF Transcription Factors, Receptors, Urokinase Plasminogen Activator, Gene Knockdown Techniques
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