Epigenetic regulation in colorectal cancer: The susceptibility of microRNAs 145, 143 and 133b to DNA demethylation and histone deacetylase inhibitors.

Abstract

Globally, colorectal cancer (CRC) is a major health concern. Despite improvements in CRC treatment, mortality rates remain high. Genetic instability and epigenetic dysregulation of gene expression are instigators of CRC development that result in genotypic differences, leading to often variable and unpredictable treatment responses. Three miRNAs, miR-143, -145 and -133b, are most commonly downregulated in CRC and are proposed here as potential tumour suppressors. Although the downregulation of these miRNAs in CRC is largely unexplained, epigenetic silencing has been postulated to be a causative regulatory mechanism. Potential epigenetic modulation of miRNA expression, by means of histone acetylation and DNA methylation, was assessed in this study by treating early (SW1116) and late stage (DLD1) CRC cells with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-Aza-2'C) and the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), respectively. Subsequent quantification of miRNA expression revealed that while all the selected miRNAs were susceptible to DNA demethylation in early- and late-stage CRC cells, susceptibility to DNA demethylation was significantly pronounced in late-stage DLD1 cells. Conversely, although histone acetylation moderately affected miRNA expression in early-stage CRC, it had a marginal effect on the expression of miRNAs in late-stage CRC cells. Overall, this study provides further understanding of the contribution of epigenetics to the regulation of putative tumour suppressor miRNAs in CRC.