The expression levels of the transcriptional regulators p300 and CtBP modulate the correlations between SNAIL, ZEB1, E‐cadherin and vitamin D receptor in human colon carcinomas

Abstract

ZEB1 and SNAIL repress CDH1 and induce epithelial-mesenchymal transition (EMT). However, SNAIL and ZEB1 also activate or regulate other target genes in different ways. For instance, vitamin D receptor (VDR), which activates CDH1 expression upon ligand binding, is repressed by SNAIL but induced by ZEB1. We examined whether the biological activity of SNAIL and ZEB1 in colon cancer is regulated by interacting cofactors. The mRNA expression levels of SNAIL and ZEB1, and of transcriptional regulators p300 and CtBP, were measured by RT-PCR in tumor and normal tissue from 101 colon carcinoma patients. Overexpression of SNAIL was associated with down-regulation of CDH1 and VDR (p 5 0.004 and p < 0.001). CDH1 correlated with VDR (r 5 0.49; p < 0.001). ZEB1 expression also correlated with VDR (r 5 0.23; p 5 0.019). However, when CtBP was strongly expressed, ZEB1 was inversely correlated with CDH1 (r 5 20.39; p 5 0.053). Furthermore, when there were elevated p300 expression levels, the correlation between expression of ZEB1 and VDR was stronger (r 5 0.38; p 5 0.070). Association between SNAIL expression and down-regulation of CDH1 and VDR was lost in tumors in which p300 and CtBP were strongly expressed. These results indicate that the levels of expression of CtBP and p300 are critical for the action of SNAIL and ZEB1, which have a pivotal role in EMT, and show the importance of CtBP and p300 for tumor progression. ' 2006 Wiley-Liss, Inc.Key words: human colorectal cancer; gene expression; p300; CtBP; epithelial-mesenchymal transition genes A large number of biological processes involve regulation of gene expression by transcriptional repression.1 ZEB1 and ZEB2 are transcriptional repressors that contain zinc-fingers motifs in their DNA binding domain, and both recognize the same E-boxes in their target genes.2,3 Despite the high homology and the identical overall gene structure of ZEB1 and ZEB2, there are differences in their pattern of expression, the organization of their repressor domains and their specificity.3 ZEB1 and ZEB2 repress a large number of regulators involved in differentiation and developmental events.2,4-12 One such regulator, E-cadherin (encode by CDH1 gene), is located in adherent junctions and contributes to the maintenance of the adhesive and polarized phenotype of epithelial cells.13 When E-cadherin is down-regulated, the epithelial cells acquire a fibroblastoid morphotype accompanied by invasion and migratory properties, which are associated with the epithelialmesenchymal transition (EMT). [14][15][16] This transition also occurs after expression of SNAIL, another transcriptional repressor with zinc-finger motifs that represses transcription of CDH1 even more efficiently than ZEB1 or ZEB2. 17,18 Moreover, ZEB1 expression is induced by SNAIL and persists after SNAIL is down-regulated in tumor cell lines. 18Vitamin D (1a,25-dehydroxyvitamin D3) induces the expression of CDH1 in cells expressing vitamin D receptors (VDRs). 19 We have recently shown that SNAIL also represses VDR expression in tumor cel...

A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial–mesenchymal transition

“…In addition to the low number of tumors analyzed, other factors might account for this lack of total correlation between the expression of the NAT/5Ј-UTR intron (and presumably Zeb2 protein) and the loss of E-cadherin; for instance, Zeb1 might be also contributing to E-cadherin down-regulation. Alternatively, repression by Zeb2 might be also dependent on the levels of the transcriptional regulators p300 and CtBP, which modulate the inverse correlation between Zeb1 and E-cadherin (Peña et al 2006). In any case, these analyses suggest that maintenance of the 5Ј-UTR intron is probably the consequence of increased transcription of the Zeb2 NAT in human tumors and further underline the relevance of our findings.…”

The Corepressor CTBP2 Is a Coactivator of Retinoic Acid Receptor/Retinoid X Receptor in Retinoic Acid Signaling

“…CTBP is part of the corepressor complex, CoREST and is involved in repression of tumor suppressor genes such as CDH1 (encoding E-cadherin), PTEN, and CDKN2A (37)(38)(39)(40)(41). In the present study, we found that suppression of Ctbp2, but not of Ctbp1, confers RA resistance, suggesting the unique attribute of Ctbp2 as a coactivator in RA signaling (Fig.…”

SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

“…It should also be remarked that transfection of ZEB1 into SW620 colon carcinoma cells results in the upregulation of endogenous VDR (Lazarova et al, 2001). In fact, we earlier observed an inverse correlation between ZEB1 and CDH1 expression in tumor tissue when the cofactor CtBP was overexpressed and a stronger direct correlation between ZEB1 and VDR when the cofactor p300 was overexpressed (Pena et al, 2006). In summary, the regulation of CDH1 and VDR seems to be different in tumor and NAT.…”