Numerous transcription factors have been identified as di...

Numerous transcription factors have been identified as direct negative regulators of transcription of CDH1 gene (also known as E-cadherin, epithelial cadherin, Cadherin-1, CADH1, or uvomorulin). Only those transcription factors reported to repress CDH1 gene transcription in at least two studies, in at least one directly, have been annotated in this pathway. These include CTBP1 (Cowger et al. 2007, Bruton et al. 2008; Deng et al. 2012; Deng et al. 2014) and CTBP2 (Zhao et al. 2007; Lee et al. 2011), DNTTIP1 (Liu et al. 2021; Wang et al. 2023), FOXQ1 (Zhang et al. 2011, Pei et al. 2015), the polycomb repressor complex PRC2 (EZH2) (Herranz et al. 2008; Oktyabri et al. 2014; Tien et al. 2015; Nolan et al. 2015; Pan et al. 2015; Rajabi et al. 2017), SNAI1 (SNAIL) (Cano et al. 2000; Batlle et al. 2000; Peinado et la. 2004; Herranz et al. 2008; Hou et al. 2010; Dong et al. 2013; Lu et al. 2014; Villarejo et al. 2014; Maturi et al. 2018), SNAI2 (SLUG) (Hajra et al. 2002; Hayashida et al, 2006; Saito et al. 2004; Saito et al, 2006; Ferrari-Amorotti et al. 2013; Villarejo et al. 2014), TCF3 (Cubillo et al. 2013; Zhu et al. 2016; Xu et al. 2021), TCF12 (Lee et al. 2012; Chen et al. 2013), TGIF2 (Hamabe et al. 2014; Yang et al. 2022), TWIST1 (Vesuna et al. 2008, Yang et al. 2012), TWIST2 (Yang et al. 2016, Wang et al. 2021), WT1 (Brett et al. 2013; Wu et al. 2013; Han et al. 2020), ZBTB33 (Jones et al. 2012, Jones et al. 2014), ZEB1 (Kokura et al. 2010; Mazda et al. 2011; Aghdassi et al. 2012; Hou et al. 2016; Sun et al. 2015; Yao et al. 2017; ), ZEB2 (Ghoumid et al. 2013; He et al. 2017), and ZNF217 (Cowger et al. 2007, Nunez et al. 2011, Si et al. 2019).

Transcription factors implicated in direct repression of CDH1 gene transcription by a single study are not shown in the pathway diagram. These include AR (Liu et al. 2008), SOX30 (Han et al. 2019), GATA1 (Li et al. 2015), MIER3 (Huang et al. 2021), TBX3 (Rodriguez et al. 2008), KLF8 (Wang et al. 2007), and GRHL3 (Zhao et al. 2016).

Hepatitis B virus (HBV)-encoded X antigen (HBx) downregulates CDH1 gene transcription by recruiting the SIN3A:HDAC histone deacetylase complex to the Snail-binding sites in the human CDH1 gene promoter (Arzumanyan et al. 2012). Hepatitis C virus (HCV) core protein facilitates binding of SNAI1 to the CDH1 gene promoter and the consequent downregulation of CDH1 gene transcription (Nie et al. 2016). Hexavalent chromium Cr(VI), a carcinogen associated with lung diseases and lung cancer, represses CDH1 gene expression through activation of CDH1 gene repressors such as SNAI1, ZEB1, and KLF8, and enhancing the binding of HDAC1 to the CDH1 gene promoter (Ding et al. 2013).

Downregulation of the CDH1 gene expression is one of the hallmarks of epithelial-to-mesenchymal transition, seen normally during development and wound healing, but also pathologically, during cancer progression (reviewed in Serrano-Gomez et al. 2016). Expression of many negative regulators of the CDH1 gene is controlled by TGF-beta signaling (Peinado et al. 2003; Choi et al. 2007; Vincent et al. 2009; Brandl et al. 2010), prostaglandin E(2) signaling (Dohadwala et al. 2006), WNT signaling (Huang et al. 2008; Khan et al. 2013), and NFκB signaling (Julien et al. 2007; Brandl et al. 2010; Hung et al. 2015).