Methylation‐mediated Transcriptional Silencing in Tumorigenesis

Abstract

Abstract Deoxyribonucleic acid (DNA) methylation of promoter CpG (cytosine/guanine) islands is a process that inhibits the expression of genes through mechanisms that interfere with transcriptional initiation. Transcriptional silencing occurs when the 5′ flanking DNA region becomes heavily methylated, either allowing transcriptional repressor proteins to directly bind to the methylated DNA region or causing a conformational change in the DNA sequence. Thus, the downstream consequence of DNA methylation is to interfere with the binding and activational activity of specific transcription factors required for gene expression. The effect of DNA hypermethylation is therefore to inhibit or reduce the expression potential of a target gene. The role of methylation in cancer has been determined by association studies where the promoter regions of tumour suppressor genes have been found to be highly methylated. This is followed by gene silencing and an increase in tumour growth. Clinical interest in the treatment of tumours has gained increased impetus because recent evidence on the use of novel therapeutic agents suggests that DNA promoter methylation is potentially reversible. This may thus allow for the development of future therapeutic intervention. Key Concepts: Epigenetic methylation is a key mechanism that can inhibit or reduce gene expression in the absence of DNA sequence variations. Aberrant DNA methylation may downregulate a gene as effectively as a pathological mutation. CpG island methylation of tumour suppressor gene promoter regions is a mechanism responsible for silencing gene expression leading to tumour development. Methylation of CpG islands can occur in regions of DNA that reside at great distances from a target gene but still lead to a reduction in gene expression. Aberrant methylation of tumour suppressor genes is potentially reversible in tumours allowing for therapeutic intervention.