N-Myc downstream-regulated gene 1 (NDRG1) plays vital roles in tumor metastasis suppression and is frequently silenced in metastatic colon cancers. NDRG1 is silenced in a highly metastatic colon cancer cell line SW620. The objective of this study was to investigate the potential mechanisms involved in silencing of the NDRG1 gene. SW480 and SW620 are two colon cancer cell lines established from the same patient with different metastatic potentials, making them an ideal model for investigation of metastatic mechanisms. Knockdown of NDRG1 in SW480 to a level that is similar to that in SW620 also modulated cell cycle and proliferation in SW480 towards the status of the highly metastatic SW620. Epigenetic mechanisms of the transcriptional control of NDRG1 were investigated. The silencing of NDRG1 in SW620 was not due to promoter hyper-methylation as bisulfite sequencing of the NDRG1 promoter showed minimal DNA methylation in both cell lines. On the other hand, chromatin immunoprecipitation showed a significantly higher level of RNA polymerase II (Pol II) association with the NDRG1 promoter in SW480 compared to SW620, in agreement with its gene expression level. The low Pol II binding at the NDRG1 promoter in SW620 was associated with gene-wide decrease in histone H4 acetylation and increase in histone H3 serine 10 phosphorylation. Meanwhile, the NDRG1 coding region showed much higher histone H3 lysine 4 methylation in SW480. In conclusion we observed unique histone modifications in two colon cancer cell lines with different metastatic potentials, indicating possible mechanisms for the down-regulation of NDRG1 in metastatic SW620.