Direct binding of ZEB1 (Zinc finger E-box-binding homeobo...

Direct binding of ZEB1 (Zinc finger E-box-binding homeobox 1, also known as deltaEF1) to E-box elements in the CDH1 (E-cadherin) gene promoter has been reported in multiple studies. Grooteclaes and Frisch 2000 demonstrated ZEB1 binding to the CDH1 gene promoter using electrophoretic mobility shift assay (EMSA) on extracts from human fibrosarcoma cell line HT1080. Eger et al. 2005 used chromatin immunoprecipitation (ChIP) to demonstrate binding of recombinant human ZEB1 to mouse Cdh1 gene in mouse mammary cells. Shirakihara et al. 2007 used EMSA to show binding of recombinant mouse Zeb1 to mouse Cdh1 gene in mouse mammary NMuMG epithelial cells. By ChIP, binding of endogenous human ZEB1 to endogenous human CDH1 gene promoter was demonstrated in human embryonic kidney cell line 293T (Sanchez-Tillo et al. 2010), glioblastoma cells (Edwards et al. 2011), pancreatic cell lines, where ZEB1 was shown to recruit histone deacetylases HDAC1 and HDAC2 to the CDH1 gene promoter (Aghdassi et al. 2012), prostate cancer cell line DU145, where ZEB1 was shown to recruit histone deacetylase SIRT1 to the CDH1 gene promoter (Byles et al. 2012), colorectal carcinoma cell line HCT116, where ZEB1 possibly recruits telomerase reverse transcriptase (TERT) to the CDH1 gene promoter (Qin et al. 2015), and human lung carcinoma cell lines, where ZEB1 recruits a corepressor protein TLE1 (Transducin-like enhancer of split 1) to the CDH1 gene promoter, leading to its deacetylation (Yao et al. 2017). TLE1 was previously shown to recruit HDACs to the CDH1 gene promoter (Yao et al. 2014, Yao et al. 2016). ZEB1 binds to the CDH11 promoter in vicinity of the SP1-binding site and prevents SP1 binding and SP1-mediated induction of CDH11 gene transcription (Zhang et al. 2022).

In response to external stimuli that activate RAS and/or PKC signaling, ZEB1 may downregulate CDH1 gene expression indirectly, in addition to direct transcriptional repression (Otake et al. 2021). ZEB1 may repress CDH1 gene transcription cooperatively with ELK3, an ETS family transcription factor, with which it was shown to form a complex (Cho et al. 2019).

ZEB1 may recruit DNA methyltransferase DNMT1 to the CDH1 gene promoter, leading to promoter hypermethylation-mediated silencing of CDH1 gene transcription (Fukagawa et al. 2015).

ZEB1 forms a complex with CTBP1 (CtBP), which is involved in ZEB1-mediated repression of genes involved in epithelial adhesion (Ichikawa et al. 2015). While two studies reported binding of CTBP1 to CDH1 gene promoter (Shi et al. 2003; Alpatov et al. 2004), it is unclear whether this binding is cooperative with ZEB1 binding. CTBP2 can also bind to ZEB1 (Furusawa et al. 1999) and was also reported to repress CDH1 gene transcription, but details have not been elucidated (Zhao et al. 2006).