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Effects of Mettl3 and Alkbh5 knockdown on small RNA export into EVs

ABSTRACT: Understanding the functional role of RNA modifications and to what extent they might regulate mature miRNA function and their secretion in extracellular vesicles (EVs) is unknown. Analysis of RNA content across a variety of EVs has shown differential miRNA enrichment when compared to parental cell expression patterns. Whether this is due to differential stability, specific regulation of miRNA export, or other mechanisms is unclear. Here, we tested whether RNA base modifications and recognition of those modifications might underlie differential miRNA export into EVs derived from KRAS mutant cell lines. We found that decreased levels of Mettl3, a writer of N6-methyladenosine (m6A) modification, altered extracellular transfer of miRNAs containing consensus sequences for m6A. Further, EVs prepared from cells expressing shRNAs against Mettl3 were incapable of conferring colony growth in 3D to wild type KRAS cells. Our data indicate that m6A modification plays an important role in miRNA export to EVs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166643 | GEO | 2021/02/12

REPOSITORIES: GEO

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Project description:METTL3-mediated RNA N6-methyladenosine (m6A) is the most prevalent modification participates in tumor initiation and progression via regulating expression of their target genes in cancers. However, its role in tumor cell metabolism remains poorly appreciated. In this study, we conducted a multi-omics analysis including m6A microarray and quantitative proteomics to explore the potential effect and mechanism of METTL3 on the metabolism in gastric cancer cells. Our results found that significant alterations in the protein and m6A modification profile which induced by METTL3 overexpression in GC cells. Gene Ontology (GO) enrichment results showed that down-regulated proteins were significantly enriched in intracellular mitochondrial oxidative phosphorylation (OXPHOS), and the Protein-Protein Interaction (PPI) network analysis found that these differentially expressed proteins were significantly associated with OXPHOS. Subsequently, a prognostic model constructed based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the high-risk group showed a worse prognosis in GC patients. Meanwhile, the Gene Set Enrichment Analysis (GSEA) showed a significant enrichment in the energy metabolism signaling pathway. Then, combined with the results of the m6A microarray analysis, the intersection molecules of DEPs and differential methylation genes (DMGs) were significantly correlated with the genes involved in OXPHOS. Besides, there were also significant differences in prognosis and GSEA enrichment between the two clusters of GC patients classified according to consensus clustering algorithm. Finally, we focused on highly expressed, highly methylated molecules regulated by METTL3 and identified three (AVEN, DAZAP2, DNAJB1) genes that were significantly associated with poor prognosis in patients with GC. These results indicated that METTL3-regulated DEPs in GC cells were significantly associated with OXPHOS. After combined with m6A microarray analysis, the results suggested that these proteins might be involved in cell energy metabolism through m6A modifications thus influencing the prognosis of GC patients. Overall, our study revealed that METTL3 involved in cell metabolism through an m6A-dependent mechanism in GC cells, and indicated a potential biomarker for prognostic prediction in GC.

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Effects of Mettl3 and Alkbh5 knockdown on small RNA export into EVs

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