Abstract
MicroRNAs (miRNAs or miRs) play crucial roles in biological and pathological processes. Some miRNAs also appear as promising biomarkers and therapeutic tools. However, the epitranscriptomic regulation of miRNAs is not yet fully elucidated in all of their fields of application. We report that adenosine methylation of miR-200b-3p inhibits its repressive function toward its mRNA targets such as XIAP by blocking the formation of the miRNA/3′ UTRmRNA duplex. Our data indicate that the adenosine methylation of miR-200b-3p is associated with the survival of glioblastoma patients. Collectively, our data support the idea that the adenosine methylation of miR-200b-3p can be used as a prodrug having a selective cytotoxicity against cancer cells (while being harmless to peripheral blood mononuclear cells [PBMCs], astrocytes, neurons, and hepatocytes).
Highlights
MicroRNAs are short non-coding RNAs that regulate protein expression toward their function as translational repressors
We focused our study on the impact of presence of N6-adenosine methylation in miRNA-200b-3p in samples of patients suffering from glioblastoma multiforme (GBM)
The m6A Methyltransferase methyltransferase-like 3 (METTL3), the m6A Demethylase FTO, and aKG Regulate the N6-Adenosine Methylation of miR200b-3p Studies have reported that miR-200 and miR-200b-3p play a role in GBM.[17,18,19,20]
Summary
MicroRNAs (miRNAs or miRs) are short non-coding RNAs (ncRNAs) that regulate protein expression toward their function as translational repressors. A variety of DNA methylation-specific methylCpG-binding domain (MBD) proteins were found to transcriptionally regulate miRNA genes.[2] Malumbres et al.[3] reported that the expression of miRNA genes is regulated through histone modifications, such as lysine methylation and acetylation Several enzymes catalyze these base modifications, including METTL1 (methyltransferase-like protein 1, UniProt: Q9UBP6) and DNMT3A (DNA [cytosine-5]-methyltransferase 3A, UniProt: Q9Y6K1), which promote the guanosine and cytosine methylation of miRNAs, respectively.[8,9] The complex methyltransferase-like 3 (METTL3)-Wilms’ tumor 1-associating protein (WTAP)- methyltransferase-like 14 (METTL14) is described as a miRNA adenosine methylase or writer, while FTO (fat mass and obesity-associated protein, UniProt: Q9C0B1) and ALKBH5 (alkylated DNA repair protein alkB homolog 5, UniProt: Q6P6C2) are described as miRNA adenosine demethylases or erasers.[5,6,10,11,12,13] Interestingly, these two enzymes are a-ketoglutarate (aKG)-dependent, suggesting that the adenosine methylation of miRNA can be regulated by the intracellular level of aKG. Xhemalce et al.[4] reported that the BCDIN3D-mediated phospho-dimethylation of miRNAs (such as precursor [pre-]miR-145) negatively regulates
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