DNA methylation of tumor suppressor miRNA genes: a lesson from the miR-34 family.

miRNA is a small ncRNA of 22-25 nucleotides, which leads to mRNA degradation or translational inhibition of its target genes. miRNAs are involved in multiple cellular processes, including cellular differentiation, proliferation and apoptosis, and hence miRNA deregulation has been implicated in disease states, including cancer. On the other hand, DNA methylation leads to gene silencing, and serves as an alternative mechanism of gene inactivation. The aberrant DNA methylation of gene promoters has been shown to result in the inactivation of tumor suppressor genes, and therefore is also implicated in carcinogenesis. This article focuses on the role of miRNA methylation, in particular miR-34a, in cancer. The article begins with an overview of DNA methylation in normal and cancer cells and deregulation of miRNA expression by DNA methylation. These discussions are followed by a description of the gene structure of the miR-34 family of miRNA genes, the tumor suppressor role of miR-34a and the deregulation of miR-34a by DNA methylation in both epithelial and hematological cancers. Moreover, the methylation of miR-34b/c in cancer is also described. Finally, the potential role of miRNA methylation as a biomarker for diagnosis, prognosis (and hence the potential of developing a risk-stratified approach) and a therapeutic target is discussed.