ZEB1
ZEB1 is a transcription factor that drives the epithelial-mesenchymal transition (EMT), the developmental program that converts a polarized, immotile epithelial cell into a motile mesenchymal one and that tumors use to invade and metastasize.
Function
ZEB1 represses the epithelial program by binding E-box sequences in the promoters of the cadherin genes - E-cadherin (CDH1) above all - and recruiting corepressors that silence them. Loss of E-cadherin dissolves adherens junctions, the cell detaches from its neighbors, and the mesenchymal program (vimentin, N-cadherin, matrix proteases) takes over. ZEB1 and the miR-200 microRNA family repress each other - ZEB1 represses miR-200, miR-200 represses ZEB1 - which makes the EMT switch bistable: a cell is in one state or the other, and the transition is a commitment. The same factor maintains stemness in mammary and neural progenitors.
In cancer
ZEB1 drives tumor invasion and metastasis: tumors at the invasive front show nuclear ZEB1, and its expression correlates with metastasis and poor prognosis in colorectal, breast, and pancreatic cancer. ZEB1 also suppresses the epithelial response to TGF-β-mediated growth arrest, so EMT converts a cytostatic signal into a motility signal. The miR-200/ZEB1 loop is a candidate target for preventing metastatic seeding.
Notes
- Human gene symbol: ZEB1; UniProt P37275; 1,124 amino acids; zinc-finger E-box-binding homeobox family.