Abstract
Simple SummaryBy the virtue of targeting multiple genes, a microRNA (miRNA) can infer variable consequences on tumorigenesis by appearing as both a tumour suppressor and oncogene. miRNAs can regulate gene expression by modulating genome-wide epigenetic status of genes that are involved in various cancers. These miRNAs perform direct inhibition of key mediators of the epigenetic machinery, such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) genes. Along with miRNAs gene expression, similar to other protein-coding genes, miRNAs are also controlled by epigenetic mechanisms. Overall, this reciprocal interaction between the miRNAs and the epigenetic architecture is significantly implicated in the aberrant expression of miRNAs detected in various human cancers. Comprehensive knowledge of the miRNA-epigenetic dynamics in cancer is essential for the discovery of novel anticancer therapeutics. Initiation and progression of cancer are under both genetic and epigenetic regulation. Epigenetic modifications including alterations in DNA methylation, RNA and histone modifications can lead to microRNA (miRNA) gene dysregulation and malignant cellular transformation and are hereditary and reversible. miRNAs are small non-coding RNAs which regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. miRNAs can target epigenetic modifier enzymes involved in epigenetic modulation, establishing a trilateral regulatory “epi–miR–epi” feedback circuit. The intricate association between miRNAs and the epigenetic architecture is an important feature through which to monitor gene expression profiles in cancer. This review summarises the involvement of epigenetically regulated miRNAs and miRNA-mediated epigenetic modulations in various cancers. In addition, the application of bioinformatics tools to study these networks and the use of therapeutic miRNAs for the treatment of cancer are also reviewed. A comprehensive interpretation of these mechanisms and the interwoven bond between miRNAs and epigenetics is crucial for understanding how the human epigenome is maintained, how aberrant miRNA expression can contribute to tumorigenesis and how knowledge of these factors can be translated into diagnostic and therapeutic tool development.
Highlights
MicroRNAs consist of short sequences of non-coding RNA which regulate translation and expression of specific target genes
Biogenesis and expression of miRNAs are known to be regulated by epigenetic modifications such as DNA methylation, RNA alterations, and histone modifications, with dysregulation of miRNAs being a hallmark of cancer initiation and metastasis [5]
We have summarised the epigenetic regulation of miRNAs in haem-malignancies and solid tumours (Tables S1 and S2), as well as the miRNAs that affect epigenetic regulation and have been reported in various cancers (Table 1)
Summary
MicroRNAs (miRNAs) consist of short sequences of non-coding RNA which regulate translation and expression of specific target genes. MiRNAs are involved in complex double-negative feedback loops where miRNA inhibition of an epigenetic regulator is controlled at the epigenetic level by the same regulator This miRNA–epigenetic feedback loop has a significant influence on gene expression levels, and dysregulation of the feedback loop can disrupt normal physiological processes, resulting in disease [7]. One way to achieve this is thorough computational data processing applications of the experimentally proven interactions between epigenetic modifications and miRNAs that can be stored as a searchable database [24,25] Such information can provide invaluable information to better understand the molecular mechanisms of “epi–miR–epi” in cancer and encourage targeted research toward epigenetics- or miRNA-related drug development
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