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.