Role of edpr1 and the znf518b factor in the development of colorectal cancer

Resumen

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Most of CRC related death is due to metastasis; therefore, finding molecular markers for prognosis of invasiveness, constitutes an appealing challenge. This work reports a significant increase in the expression of the ZNF518B and EPDR1 genes and their major splicing isoforms in tumour tissues in a commercial cDNA array. The canonical isoforms were also up-regulated in tumour tissues of a prospective cohort of 101 patients of Hospital Clínico de Valencia when compared with adjacent tissues. EPDR1 encodes a protein related to ependymins, glycoproteins involved in intercellular contacts. ZNF518B, encodes a putative zinc-finger transcription factor. These genes are only poorly known. After a thorough statistical model, this work describes that EPDR1 up-regulation correlates with the TNM staging parameters, especially T and M. Functional analyses by silencing or overexpressing these genes in CRC cell lines highlight their role in invasiveness, dissemination and EMT of the cells. Both, expression and functional analysis support the inclusion of EPDR1 and ZNF518B in panels of genes used to improve molecular subtyping of CRC. In this line, overexpression of EPDR1 was observed in CMS3 and CMS4 subtypes, while the gene was under-expressed in CMS1. Next, the regulation of both genes in CRC cell lines was studied. Nucleosomal organisation over the transcription start site and the differential presence of the epigenetic marks H3K9ac, H3K27ac, H3K4me3 and H3K9me3 correlate with ZNF518B expression. Inhibition of histone deacetylases increases the transcription of the gene. Therefore, ZNF518B, apart from being a candidate for invasiveness prognosis in CRC, may be a target for epigenetic drugs. The expression of EPDR1 is regulated by DNA methylation and by miRNA. Present work opens the way to further studies to fully exploit the therapeutic potentiality of these genes in CRC.