The Importance of Epigenetic Modification of RNA in miRNA Maturation and Breast Cancer
MicroRNAs (miRNAs) are single-stranded RNA molecules 18-24 bases in length that are important for the regulation of many biological processes by posttranscriptionally interfering with gene expression. MiRNAs generally regulate gene expression by either facilitating mRNA degradation or repressing translation. Generation of the mature and active form of miRNAs requires the cleavage of pre-miRNA molecules by the RNase III enzymes Drosha and Dicer. Xhemalce et al. identified that BCDIN3D, a previously uncharacterized enzyme, is an RNA methyltransferase. BCDIN3D methylates the 5’ monophosphate of pre-miRNAs, generating 5’ phospho-dimethylated RNA molecules. Pre-miRNAs that are 5’ phospho-dimethylated by BCDIN3D did not efficiently associate with Dicer and therefore were not efficiently processed, leading to a decrease in mature miRNA levels and a corresponding increase in the levels of the respective pre-miRNAs. The authors suggest that pre-miRNA methylation by BCDIN3D might be widespread and potentially be responsible for regulating the processing of many miRNAs, and therefore would be important for numerous cellular processes and human disorders, including breast cancer.
A previous study revealed that BCDIN3D mRNA was overexpressed in breast cancer tissue and high levels of BCDIN3D were found to be associated with a cellular invasion phenotype. In this current report, the authors demonstrated that depletion of BCDIN3D in breast cancer cells using RNAi resulted in increased levels of certain miRNAs, such miR-145, and a reduction in the tumorigenic potential of these cells. The authors’ results indicate that BCDIN3D directly methylates pre-miR-145, thus inhibiting its recognition and processing by Dicer, and therefore increasing tumorigenic phenotype of cells by reducing levels of mature miR-145. The relationship between BCDIN3D and miR-145 levels and tumorgenicity phenotypes suggests that BCDIN3D acts as an oncoprotein and miR-145 as a tumor suppressor.
This report suggests that BCDIN3D may be integral in the regulation of multiple miRNAs, suggesting that 5’ methylation of pre-miRNAs might be an epigenetic modification that adds yet another layer of control over miRNA expression and maturation. Furthermore, the discovery and characterization of an enzyme that inhibits Dicer-dependent processing of miRNAs could provide a target for future therapies of breast cancer and other human diseases.
Xhemalce B, Robson SC, & Kouzarides T (2012). Human RNA methyltransferase BCDIN3D regulates microRNA processing. Cell, 151 (2), 278-88 PMID: 23063121