E-cadherin modulates Wnt-dependent transcription in colorectal cancer cells but does not alter Wnt-independent gene expression in fibroblasts.
E-cadherin mediates homophilic adhesion of epithelial cells and is a major determinant of epithelial differentiation during embryonic development and tumor progression. At cell junctions, E-cadherin associates with beta-catenin, which also functions as a transcriptional co-activator of the canonical Wnt signaling pathway by interacting with TCF transcription factors. Here, we have analyzed whether E-cadherin plays a role in the control of gene expression in Wnt-dependent and -independent cellular systems. In DLD-1 colorectal cancer cells, which show constitutive activation of Wnt signaling and exhibit E-cadherin-based cell contacts, the siRNA-mediated knock-down of E-cadherin led to the disturbance of cell junctions, translocation of beta-catenin to the nucleus and an enhancement of beta-catenin/TCF-dependent reporter activity. In L929 fibroblasts, which are deficient in Wnt signaling and E-cadherin-mediated cell adhesion, ectopic expression of E-cadherin induced the stabilization of beta-catenin at the cell junctions and caused marked alterations in cellular morphology and phenotype. However, E-cadherin did not significantly change the transcriptional program of these cells as revealed by DNA microarray analysis. Our data indicate that E-cadherin may modulate Wnt-dependent gene expression by regulating the availability of beta-catenin but has a surprisingly small impact on gene expression in the absence of Wnt signaling.
Kuphal
Felix
F
Department of Experimental Medicine II, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen, Glueckstr. 6, 91054 Erlangen, Germany.
Behrens
Jürgen
J
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D048430:Cell Shape / Q000235:genetics; D005576:Colforsin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D019108:Tight Junctions / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
D015820:Cadherins; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D005576:Colforsin; D004318:Doxycycline