ZEB1 represses CDH1 gene transcription

Stable Identifier
R-HSA-9764778
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
3/5
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ZEB1 represses CDH1 gene transcription
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Direct repression of CDH1 gene transcription was first demonstrated separately for ZEB1 and SMARCA4 (BRG1), followed by reports that ZEB1 recruits SMARCA4, a component of the SWI/SNF chromatin remodeling complex, to the CDH1 gene promoter to represses CDH1 gene transcription. Transcription from the human CDH1 gene promoter fused to the luciferase gene is increased upon siRNA-mediated knockdown of endogenous ZEB1 in human prostate adenocarcinoma cell line PC-3 (Mazda et al. 2011). In human bronchoepithelial cells 16HBE, SMARCA4 was shown to bind to the CDH1 gene promoter by chromatin immunoprecipitation (ChIP) and shRNA-mediated knockdown of SMARCA4 leads to increased CDH1 gene transcription (Wang et al. 2017). ZEB1-mediated transcriptional repression of CDH1 gene, as shown by a luciferase reporter assay, is enhanced in the presence of SMARCA4, which is recruited to the CDH1 gene promoter by binding to ZEB1. For the luciferase reporter assay, human CDH1 promoter fused with the luciferase gene, along with human recombinant ZEB1 and SMARCA4, was transfected into human mammary carcinoma cell line MCF7 and human ovarian carcinoma cell line C33a (Sanchez-Tillo et al. 2010). Cooperative repression of the CDH1 gene transcription by ZEB1 and ZEB1-recruited SMARCA4 was also demonstrated in the human bronchoepithelial 16HBE cells by a luciferase reporter assay using human CDH1 gene promoter regions with or without ZEB1-binding sites fused to the luciferase gene, alongside shRNA-mediated knockdown of SMARCA4 (Wang et al. 2022).

ZEB1-mediated repression of CDH1 gene transcription has also been shown to involve histone deacetylases HDAC1 and HDAC2 (Aghdassi et al. 2012). HDAC1 was shown to be recruited to the CDH1 gene promoter by the transcriptional corepressor TLE1 (Yao et al. 2014) in a ZEB1-dependent manner (Yao et al. 2016, Yao et al. 2017), leading to deacetylation of the CDH1 gene promoter (Yao et al. 2017).

ZEB1-mediated repression of the CDH1 gene transcription is enhanced by the recruitment of SETD8 (SET8) histone methyltransferase to the CDH1 gene promoter (Hou et al. 2016).

MPHOSPH8 (also known as M-phase phosphoprotein 8 or MPP8) binds to the CDH1 gene promoter and represses CDH1 gene expression (Kokura et al. 2010) in a ZEB1-dependent manner (Sun et al. 2015). MPHOSPH8 was shown to recruit histone deacetylase SIRT1 to ZEB1 at the CDH1 gene promoter, resulting in histone deacetylation, which contributes to CDH1 gene repression (Sun et al. 2015).
Literature References
PubMed ID Title Journal Year
25446087 TLE1 promotes EMT in A549 lung cancer cells through suppression of E-cadherin

Yao, X, Ireland, SK, Pham, T, Temple, B, Chen, R, Raj, MH, Biliran, H

Biochem Biophys Res Commun 2014
25870236 MPP8 and SIRT1 crosstalk in E-cadherin gene silencing and epithelial-mesenchymal transition

Sun, L, Kokura, K, Izumi, V, Koomen, JM, Seto, E, Chen, J, Fang, J

EMBO Rep 2015
20418909 ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1

Sánchez-Tilló, E, Lázaro, A, Torrent, R, Cuatrecasas, M, Vaquero, EC, Castells, A, Engel, P, Postigo, A

Oncogene 2010
26717907 SET8 induces epithelial‑mesenchymal transition and enhances prostate cancer cell metastasis by cooperating with ZEB1

Hou, L, Li, Q, Yu, Y, Li, M, Zhang, D

Mol Med Rep 2016
22205962 E-cadherin is transcriptionally activated via suppression of ZEB1 transcriptional repressor by small RNA-mediated gene silencing

Mazda, M, Nishi, K, Naito, Y, Ui-Tei, K

PLoS One 2011
29069783 TLE1 inhibits anoikis and promotes tumorigenicity in human lung cancer cells through ZEB1-mediated E-cadherin repression

Yao, X, Pham, T, Temple, B, Gray, S, Cannon, C, Hardy, C, Fletcher, K, Ireland, SK, Hossain, A, Chen, R, Abdel-Mageed, AB, Biliran, H

Oncotarget 2017
28801844 Brg1 inhibits E-cadherin expression in lung epithelial cells and disrupts epithelial integrity

Wang, T, Zou, W, Niu, C, Ding, F, Wang, Y, Cai, S, Zhu, H, Tian, D, Dai, J, Liu, E, Lu, Q, Fu, Z, Zou, L

J Mol Med (Berl) 2017
35138000 ZEB1 recruit Brg1 to regulate airway remodeling epithelial-mesenchymal transition in asthma

Wang, T, Peng, B, Luo, T, Tian, D, Zhao, Z, Fu, Z, Li, Q

Exp Physiol 2022
27655370 The Anoikis Effector Bit1 Inhibits EMT through Attenuation of TLE1-Mediated Repression of E-Cadherin in Lung Cancer Cells

Yao, X, Pham, T, Temple, B, Gray, S, Cannon, C, Chen, R, Abdel-Mageed, AB, Biliran, H

PLoS One 2016
Participants
Input
Output
Participates
as an event of
This event is regulated
Negatively by
Regulator
ZEB1:CDH1 gene, SMARCA4:ZEB1:CDH1 gene, HDAC1,(HDAC2):TLE1:ZEB1:CDH1 gene, (SETD8:ZEB1:CDH1 gene, SIRT1:MPHOSPH8:ZEB1:CDH1 gene) [nucleoplasm] (Homo sapiens)
Active Unit
SMARCA4 [nucleoplasm]
ZEB1 [nucleoplasm]
HDAC1,(HDAC2) dimers [nucleoplasm]
TLE1 tetramer [nucleoplasm]
SETD8 [nucleoplasm]
MPHOSPH8 [nucleoplasm]
SIRT1 [nucleoplasm]
Authored
Orlic-Milacic, M  (2022-02-14)
Created
Orlic-Milacic, M  (2022-02-14)
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