Zeb1 Regulates E-cadherin and Epcam (Epithelial Cell Adhesion Molecule) Expression to Control Cell Behavior in Early Zebrafish Development*

Abstract

Background: Regulation of cell adhesion is important for embryonic development and to prevent cancer metastasis.

Results: Zeb1 controls cell adhesion in zebrafish embryos and human cancer cell lines through transcriptional repression of E-cadherin, Epcam, and miR-200s.

Conclusion: Zeb1 fine-tunes E-cadherin- and Epcam-mediated cell adhesion to control cell behavior during gastrulation.

Significance: Conserved cell adhesion regulation mechanisms are crucial for understanding development and cancer invasion.

Abstract

The ZEB1 transcription factor is best known as an inducer of epithelial-mesenchymal transitions (EMT) in cancer metastasis, acting through transcriptional repression of CDH1 (encoding E-cadherin) and the EMT-suppressing microRNA-200s (miR-200s). Here we analyze roles of the ZEB1 zebrafish orthologs, Zeb1a and Zeb1b, and of miR-200s in control of cell adhesion and morphogenesis during gastrulation and segmentation stages. Loss and gain of function analyses revealed that Zeb1 represses cdh1 expression to fine-tune adhesiveness of migrating deep blastodermal cells. Furthermore, Zeb1 acts as a repressor of epcam in the deep cells of the blastoderm and may contribute to control of epithelial integrity of enveloping layer cells, the outermost cells of the blastoderm. We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter. Thus, Zeb1 proteins employ several evolutionary conserved mechanisms to regulate cell-cell adhesion during development and cancer.