title: Long-range epigenetic silencing associates with deregulation of Ikaros targets in colorectal cancer cells.
abstract: Transcription factors are common targets of epigenetic inactivation in human cancer. Promoter hypermethylation and subsequent silencing of transcription factors can lead to further deregulation of their targets. In this study, we explored the potential epigenetic deregulation in cancer of Ikaros family genes, which code for essential transcription factors in cell differentiation and exhibit genetic defects in hematologic neoplasias. Unexpectedly, our analysis revealed that Ikaros undergoes very specific promoter hypermethylation in colorectal cancer, including in all the cell lines studied and around 64% of primary colorectal adenocarcinomas, with increasing proportions in advanced Duke's stages. Ikaros hypermethylation occurred in the context of a novel long-range epigenetic silencing (LRES) region. Reintroduction of Ikaros in colorectal cancer cells, ChIP-chip analysis, and validation in primary samples led us to identify a number of direct targets that are possibly related with colorectal cancer progression. Our results not only provide the first evidence that LRES can have functional specific effects in cancer but also identify several deregulated Ikaros targets that may contribute to progression in colorectal adenocarcinoma.
authors: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, Barcelona, Spain.
authors: Biola M
authors: BM
authors: Javierre
authors: Javier
authors: J
authors: Rodriguez-Ubreva
authors: Fatima
authors: F
authors: Al-Shahrour
authors: Marina
authors: M
authors: Corominas
authors: Osvaldo
authors: O
authors: Graña
authors: Laura
authors: L
authors: Ciudad
authors: Xabier
authors: X
authors: Agirre
authors: David G
authors: DG
authors: Pisano
authors: Alfonso
authors: A
authors: Valencia
authors: Jose
authors: J
authors: Roman-Gomez
authors: Maria Jose
authors: MJ
authors: Calasanz
authors: Felipe
authors: F
authors: Prosper
authors: Manel
authors: M
authors: Esteller
authors: Rogelio
authors: R
authors: Gonzalez-Sarmiento
authors: Esteban
authors: E
authors: Ballestar
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D045325:HCT116 Cells; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor