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Review
. 2020 Oct 11;12(10):2922.
doi: 10.3390/cancers12102922.

Regulatory Mechanisms of Epigenetic miRNA Relationships in Human Cancer and Potential as Therapeutic Targets

K M Taufiqul Arif  1 , Esther K Elliott  1 , Larisa M Haupt  1 , Lyn R Griffiths  1
Affiliations
Review

Regulatory Mechanisms of Epigenetic miRNA Relationships in Human Cancer and Potential as Therapeutic Targets

K M Taufiqul Arif et al. Cancers (Basel). .

Abstract

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.

Keywords: bioinformatics; cancer; epigenetics; microRNA; therapeutics.

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Conflict of interest statement

The authors declare no conflict of interests.

Figures

Figure 1
Figure 1
miRNA epigenetic crosstalk. Association of miRNAs with epigenetic regulators involved in the processes of DNA methylation and histone modification. miRNA-mediated alteration of these regulators causes aberrant DNA methylation and chromatin modification. These distorted conditions modify the expression of genes that are involved in modulating the epigenetic machinery and can also affect miRNA expression.
Figure 2
Figure 2
A miRNA-epigenetic network analysis. The diagram represents a network analysis outcome conducted in miRNet suite among 555 miRNAs with 48 epigenetic modifiers hosted by the tool itself. Among those modifiers, DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) showed a strong connection with miRNAs and other modifiers. The enlisted 48 modifiers used were as follows: AML1-ETO oncoprotein/HDAC1/DNMTs/MeCP2, AML1/ETO protein, CARM1, CBP, DNMT-1, DNMT-1/DNMT-3a/DNMT-3b, DNMT-1/DNMT-3b, DNMT-1/DNMT-3B, DNMT-1/MeCP2, DNMT-1/MLL, DNMT-3a, DNMT-3a/DNMT-3b, DNMT-3a/DNMT-3b/DNMT-1, DNMT-3b, DNMTs, Egr2/Jardi1b, EVI1/DNMT-3b, EZH2, EZH2/G9a/HDAC, HDAC1, HDAC1/AP-1, HDAC1/HDAC2, HDAC1/HDAC2/HDAC4, HDAC1/HDAC3/EP300, HDAC3/Myc, HDAC4, HDAC4/HDAC5, HDAC4/SP1, HDACs, HER2, IL-6, JARID1B, Kindlin 2/DNMT-3, MBD1, MBD2, MeCP2, SUZ12/BMI1, Mel-18/DNMT-1, MLL fusion proteins, MYC/HDAC3/EZH2, MYST3, p50 p53, PRC2, PRMT5, RNAPII, sp1, and SUV39H1.
Figure 3
Figure 3
An overview of the therapeutic application of miRNA-based agents used in the prevention of tumour progression. These agents target and regulate the miRNA of interest, resulting in either inhibition of an OncomiR or upregulation of a tumour suppressor gene. Five commonly utilised therapeutic miRNA agents are displayed above showing (A) anti-miRs, miRNA sponges and miRNA masks used to suppress oncomiRs by inhibiting miRNA binding to mRNA. miRNA mimics and molecule inhibitor drugs can be used to inhibit DNMT enzymatic activity and trigger its degradation, thereby reducing oncomiR expression and development of malignancy. Similarly, histone deacetylase inhibitors (HDACis) can be used to block tumorigenesis. (B) miRNA mimics can also be utilised to mimic the activity of tumour suppressor miRNA in malignancies to reduce or suppress tumorigenesis.
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