Expanding roles of ZEB factors in tumorigenesis and tumor progression

Abstract

The ZEB family of transcription factors regulates key factors during embryonic development and cell differentiation but their role in cancer biology has only more recently begun to be recognized. Early evidence showed that ZEB proteins induce an epithelial-to-mesenchymal transition linking their expression with increased aggressiveness and metastasis in mice models and a wide range of primary human carcinomas. Reports over the last few years have found that ZEB proteins also play critical roles in the maintenance of cancer cell stemness, control of replicative senescence, tumor angiogenesis, overcoming of oncogenic addiction and resistance to chemotherapy. These expanding roles in tumorigenesis and tumor progression set ZEB proteins as potential diagnostic, prognostic and therapeutic targets.

Keywords: Cancer; E-cadherin; EMT; ZEB1; ZEB2; cancer stem cells; chemotherapy resistance; transcription; tumor invasiveness.

Figure 1

Scheme of the domain structure and main binding proteins of human ZEB1 and ZEB2. Percentages indicate identity at the amino acid level (GenBank accession numbers U12170 and AB011141, respectively). Proteins labeled in green represent coactivators, in red corepressors and in blue other transcription factors. Nt-ZFC: N-terminal zinc finger cluster. SID: Smad-interacting domain; Mid-ZFC: mid zinc finger cluster; HD: Homeodomain; CID: CtBP-interacting domain; Ct-ZFC: C-terminal zinc finger cluster. High degree of amino acid identity between ZEB1 and ZEB2 is mostly restricted to the Nt-ZFC and C-ZFC (89% and 95%, respectively), the SID (42%) and the homeodomain (46%).

Figure 2

ZEB1 and ZEB2 could act as either transcriptional repressors or activators depending on the target gene and tissue. Transcriptional repression and activation is achieved through differential recruitment of cofactors. Post-transcriptional modifications of ZEB1 and ZEB2 alter the set of coactivators and corepressors bound and switch both proteins from transcriptional repressors to activators.

Figure 3

Schematic representation of the evolution of a carcinoma in situ into an invasive carcinoma. Invasion of cancer cells into the surrounding stroma involves a complex process by which they lose their epithelial characteristics and acquire instead a mesenchymal phenotype as part of the EMT. ZEB1 is not present in normal epithelial cells or at the center of well-differentiated carcinomas but is expressed by invasive cancer stem cells undergoing an active EMT at the tumor front of several types of carcinomas. ZEB1 also regulates several components of the basement membrane, which breakdown is required for cancer cells to invade the surrounding stroma.

Figure 4

ZEB1 and β-catenin colocalize at the nucleus of invasive cancer cells at the tumor front of colorectal carcinomas. While in epithelial cells of well-differentiated areas of colorectal carcinomas β-catenin has a membranous/ cytoplasmic distribution it becomes mostly nuclear in these invasive cancer cells. ZEB1 (green, E-20 antibody, Santa Cruz Biotechnology) and β-catenin (red, Ab6032 antibody, Abcam) colocalize (yellow, merge panel) in invasive cancer cells of a sporadic colorectal carcinoma [35,78]. Labeling with 4',6-diamidino-2-phenylindole (DAPI) is also shown. Scale bar represents 25 μm.