Genome-wide epigenetic regulation of miRNAs in cancer.

Aberrant microRNA (miRNA) expression contributes to tumorigenesis and cancer progression. Although the number of reported deregulated miRNAs in various cancer types is growing fast, the underlying mechanisms of aberrant miRNA regulation are still poorly studied. Epigenetic alterations including aberrant DNA methylation deregulate miRNA expression, which was first shown by reexpression of miRNAs upon pharmacologic DNA demethylation. However, studying the influence of DNA methylation on miRNA transcription on a genome-wide level was hampered by poor miRNA promoter annotation. Putative miRNA promoters were identified on a genome-wide level by using common promoter surrogate markers (e.g., histone modifications) and were later validated as such in different tumor entities. Integrating promoter datasets and global DNA methylation analysis revealed an extensive influence of DNA hyper- as well as hypomethylation on miRNA regulation. In this review, we summarize the current knowledge of the field and discuss recent efforts to map miRNA promoter sequences and to determine the contribution of epigenetic mechanisms to the regulation of miRNA expression. We discuss examples of tumor suppressive and oncogenic miRNAs such as the miR-34 and miR-21 family, respectively, which highlight the complexity and consequences of epigenetic miRNA deregulation.