DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer

Abstract

MicroRNAs (miRNAs) are recognized as being central players in many biological processes and cellular pathways. Their roles in disease have been highlighted first by observation of their aberrant expression profiles in human tumors, and then by in vitro and in vivo functional studies in transformed cells and model organisms. One of the most commonly observed features of miRNAs in malignancies is a defect in their production. Although several causes may be associated with this phenomenon, such as upstream oncogenic/tumor-suppressor defects and alterations in the miRNA-processing machinery, epigenetic inactivation is the prime suspect. The number of miRNAs with putative growth-inhibitory functions undergoing promoter CpG island hypermethylation in human cancer is growing fast and more detailed biological studies are necessary. The recognition of miR-124a and miR-34b/c as bona fide tumor-suppressor miRNAs undergoing DNA methylation-associated silencing in a wide spectrum of human neoplasms is a good starting point to be followed by other candidate miRNAs. Most importantly, even at this early stage, the transcriptional repression of miRNAs by hypermethylation of their corresponding promoter loci seems to be a common feature of all human tumors. This will have translational consequences for the management of the disease.

Figure 1

The miRNA biosynthesis pathway from the nucleus to the cytosol. Ago, Argonaute protein; DGCR8, DiGeorge Syndrome Critical Region Gene-8; miRNA, microRNA; ORF, open reading frame; TAR-binding protein; UTR, untranslated region; XPO5, exportin-5; TRBP.

Figure 2

Mechanisms by which miRNAs regulate gene expression within a cell and in neighboring cells. Ago, Argonaute protein; ORF, open reading frame; RISC, RNA-induced silencing complex; TRBP, TAR-binding protein; UTR, untranslated region.

Figure 3

Aberrant DNA methylation patterns in human cancer. Heavily methylated repetitive sequences undergo hypomethylation events in transformed cells that might cause genome instability (right panel), whereas unmethylated promoter CpG islands of coding genes and miRNAs with tumor-suppressor features become hypermethylated and silenced in cancer cells (left panel).