title: 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 = 0.004 and p < 0.001). CDH1 correlated with VDR (r = 0.49; p < 0.001). ZEB1 expression also correlated with VDR (r = 0.23; p = 0.019). However, when CtBP was strongly expressed, ZEB1 was inversely correlated with CDH1 (r = -0.39; p = 0.053). Furthermore, when there were elevated p300 expression levels, the correlation between expression of ZEB1 and VDR was stronger (r = 0.38; p = 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.
authors.affiliation: Department of Medical Oncology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Peña
authors.forename: José Miguel
authors.initials: JM
authors.lastname: García
authors.forename: Vanesa
authors.initials: V
authors.lastname: García
authors.forename: Javier
authors.initials: J
authors.lastname: Silva
authors.forename: Gemma
authors.initials: G
authors.lastname: Domínguez
authors.forename: Rufo
authors.initials: R
authors.lastname: Rodríguez
authors.forename: Constanza
authors.initials: C
authors.lastname: Maximiano
authors.forename: Antonio
authors.initials: A
authors.lastname: García de Herreros
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.forename: Félix
authors.initials: F
authors.lastname: Bonilla
mesh_terms: D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics*; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000071799:Zinc Finger E-box-Binding Homeobox 1; D050880:p300-CBP Transcription Factors / Q000235:genetics*
chemical_list: D015820:Cadherins; D017931:DNA Primers; D018398:Homeodomain Proteins; D018167:Receptors, Calcitriol; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D050880:p300-CBP Transcription Factors