Abstract
Most of colorectal cancer CRC-related death is due to metastasis and the finding of markers for prognosis of invasiveness, constitutes an appealing challenge. Here, after analysing cDNA array containing 43 tumour and 5 normal mucosa samples, we report that the expression of the ZNF518B gene as a whole and that of its two major splicing isoforms are significantly increased in tumours. The canonical isoform was also up-regulated in a patients’ cohort containing 70 tumour and 69 adjacent tissue samples. The effects of silencing ZNF518B on the phenotype of CRC cell lines were then studied. The gene does not affect cell proliferation, but plays a significant role in cell migration and invasiveness and induces changes in the epithelial-to-mesenchymal transition markers, suggesting that ZNF518B favours tumour cell dissemination. To study the regulation of the gene, transcription-related changes in nucleosomal organisation and epigenetic marks around the transcriptional start site were analysed. The positioning of a nucleosome over the transcription start site and the differential presence of the epigenetic marks H3K9ac, H3K27ac, H3K4me3 and H3K9me3 correlate with gene expression. Inhibition of histone deacetylases increases the transcription of ZNF518B, which may be a candidate for invasiveness prognosis in CRC and a target for epigenetic drugs.
Highlights
Colorectal cancer (CRC) ranks among the most prevalent carcinomas worldwide and 1.4 million new cases are diagnosed each year[1]
The expression of the ZNF518B gene as a whole and of its isoforms 1 and 2 was determined by RT-qPCR in all the samples. Both the whole gene and its isoforms are significantly overexpressed in human CRC at all stages but no significant differences were observed from one stage to another (Fig. 1)
Only the results obtained with the canonical isoform from non-paired 70 tumour and 69 non-tumour adjacent samples are presented in Fig. 2, which shows that, in agreement with the data obtained from the cDNA array, ZNF518B is significantly up-regulated in human CRC
Summary
Colorectal cancer (CRC) ranks among the most prevalent carcinomas worldwide and 1.4 million new cases are diagnosed each year[1]. We have reported that ZNF518B gene is differentially expressed in some human CRC cell lines[3], but the knowledge on the role and properties of the gene is very limited. It is clear from sequence data that isoform 1 encodes a zinc-finger protein, a putative transcriptional factor for which the identification of its possible targets remains to be determined. The enzyme is overexpressed in CRC tissues when compared to paired normal epithelium and its down-regulation inhibits proliferation of cancer cells[9]. Isoform 1 is up-regulated in a larger patients’ cohort In view of these results, we further describe in this paper that ZNF518B is involved in migration and invasiveness of CRC cell lines, and that the regulation of gene expression takes place at a chromatin level
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