ZEB1

ZEB1 Full Name

zinc finger E-box binding homeobox 1

ZEB1 Introduction

ZEB1 (zinc finger E-box binding homeobox 1, also known as TCF8 or δEF1) is a member of the ZEB family of transcription factors, which includes ZEB1 and ZEB2, characterized by the presence of multiple zinc finger domains and a homeodomain. The gene is located on chromosome 10p11.22 and encodes a protein of 1,124 amino acids with a molecular weight of approximately 124 kDa. ZEB1 functions as a master regulator of epithelial-mesenchymal transition (EMT), a cellular process in which epithelial cells lose their cell-cell adhesion and polarity and acquire mesenchymal properties including increased migration and invasion. During EMT, ZEB1 represses the expression of E-cadherin (CDH1) and other epithelial markers by binding to E-box sequences in their promoters, and induces the expression of mesenchymal markers including vimentin, N-cadherin, and fibronectin. ZEB1 also plays essential roles in embryonic development, particularly in mesodermal patterning, neural crest development, and myogenesis. In adults, ZEB1 expression is normally restricted to certain tissues but is frequently reactivated in cancer, where it promotes tumor progression, metastasis, stemness, and chemoresistance. ZEB1 also functions as a key regulator of the immune response, T-cell differentiation, and tissue fibrosis, and its dysregulation has been implicated in various non-malignant diseases.

Figure 1. Schematic structure of ZEB1.

Core Physiological Functions of ZEB1
ZEB1 performs irreplaceable physiological functions in embryonic development, tissue homeostasis, cell differentiation, and wound repair in normal human organisms. During embryonic development, ZEB1 precisely regulates the EMT process required for gastrulation, neural crest cell migration, and organ morphogenesis, supporting the normal formation and structural maturation of multiple organs and tissues. In adult tissues, basal ZEB1 expression maintains the stemness and differentiation potential of tissue stem cells, facilitating continuous tissue renewal and homeostasis maintenance. Moreover, ZEB1 is a key participant in physiological wound healing and tissue repair; it transiently activates EMT programs to promote cell migration and tissue reconstruction after tissue injury, effectively accelerating wound closure and extracellular matrix remodeling. In addition, ZEB1 modulates normal immune cell differentiation and inflammatory homeostasis, balancing tissue repair responses and preventing excessive fibrotic deposition under physiological conditions, ensuring the stable operation of various organ systems.

Biological Functions in Epithelial-Mesenchymal Transition and Development
ZEB1 is the master transcriptional regulator of epithelial-mesenchymal transition (EMT), a developmental program that is aberrantly reactivated in cancer. During EMT, ZEB1 binds to E-box sequences in the E-cadherin (CDH1) promoter, recruits co-repressors including CtBP, and represses E-cadherin transcription. Loss of E-cadherin disrupts adherens junctions, leading to loss of cell-cell adhesion and acquisition of a mesenchymal phenotype. ZEB1 also represses other epithelial markers including tight junction proteins (claudins, occludin), desmosomal proteins, and mucins, while indirectly inducing the expression of mesenchymal markers including vimentin, N-cadherin, fibronectin, and matrix metalloproteinases (MMPs). The transition to a mesenchymal state enables cells to detach from the primary tumor, invade through the extracellular matrix, intravasate into blood or lymphatic vessels, and metastasize to distant organs. In addition to promoting EMT, ZEB1 also induces a stem cell-like state by repressing stemness-inhibiting microRNAs (including miR-200 family and miR-203) and activating stemness-promoting genes. Cells that have undergone ZEB1-mediated EMT exhibit properties of cancer stem cells (CSCs), including self-renewal capacity, tumor initiation ability, and resistance to chemotherapy and radiation. In embryonic development, ZEB1 is essential for the formation of the mesoderm and neural crest. Zeb1 knockout mice die perinatally with severe defects in skeletal patterning, neural tube closure, and immune system development. ZEB1 also plays critical roles in T-cell differentiation, where it regulates the balance between Th17 and Treg cells, and in tissue fibrosis, where it promotes the transition of fibroblasts to myofibroblasts.

Alternate Names for ZEB1

ZEB1; zinc finger E-box binding homeobox 1; BZP; TCF8; AREB6; FECD6; NIL2A; PPCD3; ZFHEP; ZFHX1A