ZEB1

ZEB1, or zinc finger E-box-binding homeobox 1, is a transcription factor encoded by the ZEB1 gene. It belongs to the ZEB family and is characterized by two clusters of C2H2-type zinc fingers at the C-terminus that bind E-box DNA sequences, enabling it to regulate a broad set of epithelial and mesenchymal genes. ZEB1 commonly acts as a transcriptional repressor by recruiting corepressors such as CtBP1/2 and chromatin-modifying complexes, and it can modulate transcription in a context-dependent manner.

A central role of ZEB1 is the promotion of epithelial-mesenchymal transition (EMT). It represses epithelial markers, notably CDH1 (E-cadherin), and supports mesenchymal programs, enabling changes in cell adhesion, motility, and invasiveness. ZEB1 activity is integrated with signaling pathways, including TGF-beta, where interaction with SMAD proteins can enhance EMT gene programs. The activity of ZEB1 is also tied to chromatin state and can involve cooperation with histone modifiers.

Regulation is complex and involves microRNAs, especially the miR-200 family, which targets ZEB1 mRNA for degradation. ZEB1 and miR-200 form a double-negative feedback loop that governs epithelial plasticity, influencing development, tissue homeostasis, and disease states.

In development, ZEB1 contributes to processes such as neural crest formation and organogenesis, while in adulthood dysregulated ZEB1 is associated with cancer progression, metastasis, therapy resistance, and fibrotic diseases. Clinically, higher ZEB1 expression often correlates with poorer prognosis in several cancers and may indicate metastatic potential.

ZEB1 is closely related to ZEB2 (SIP1); both regulate EMT and share targets but can have distinct expression patterns and roles.