Integrative proteomics and m6A microarray analyses of the signatures induced by METTL3 reveals prognostically significant in gastric cancer by affecting cellular metabolism

Abstract

METTL3-mediated RNA N6-methyladenosine (m6A) is the most prevalent modification that participates in tumor initiation and progression via governing the expression of their target genes in cancers. However, its role in tumor cell metabolism remains poorly characterized. In this study, m6A microarray and quantitative proteomics were employed to explore the potential effect and mechanism of METTL3 on the metabolism in GC cells. Our results showed that METTL3 induced significant alterations in the protein and m6A modification profile in GC cells. Gene Ontology (GO) enrichment indicated that down-regulated proteins were significantly enriched in intracellular mitochondrial oxidative phosphorylation (OXPHOS). Moreover, the protein-protein Interaction (PPI) network analysis found that these differentially expressed proteins were significantly associated with OXPHOS. A prognostic model was subsequently constructed based on the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, and the high-risk group exhibited a worse prognosis in GC patients. Meanwhile, Gene Set Enrichment Analysis (GSEA) demonstrated 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 molecules of OXPHOS. Besides, there were significant differences in prognosis and GSEA enrichment between the two clusters of GC patients classified according to the consensus clustering algorithm. Finally, highly expressed and highly methylated molecules regulated by METTL3 were analyzed and three (AVEN, DAZAP2, DNAJB1) genes were identified to be significantly associated with poor prognosis in GC patients. These results signified 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 implicated in cell energy metabolism through m6A modifications thus influencing the prognosis of GC patients. Overall, our study revealed that METTL3 is involved in cell metabolism through an m6A-dependent mechanism in GC cells, and indicated a potential biomarker for prognostic prediction in GC.

METTL3-mediated m6A modification of lncRNA SNHG3 accelerates gastric cancer progression by modulating miR-186-5p/cyclinD2 axis

“…5–11 METTL3 has been proved to be upregulated in multiple malignances including GC, 5,12–17 and indicate poor prognosis, 5,14,16,17 but it is downregulated and associated with favorable prognosis in RCC. 19 In the present study, in accordance with previous reports, 5,20–23 we found that elevated expression of METTL3 was related to poor overall survival, acting as a prognostic marker in GC. METTL3 might be a potential prognostic factor in GC.…”

Critical roles and clinical perspectives of RNA methylation in cancer

“…Notably, METTL3 upregulates AVEN and DNAJB1 levels, contributing to a poorer clinicopathological grade and stage in GC patients. These findings suggest that METTL3 influences GC cell metabolism, particularly OXPHOS, and hold promise for developing novel therapeutic targets and predictive markers in GC 457 . Additionally, the upregulation of IGF2BP1 in GC tissues is associated with enhanced aerobic glycolysis and malignant behaviors of GC cells and with a poor prognosis in patients with GC.…”

“…These findings suggest that METTL3 influences GC cell metabolism, particularly OXPHOS, and hold promise for developing novel therapeutic targets and predictive markers in GC. 457 Additionally, the upregulation of IGF2BP1 in GC tissues is associated with enhanced aerobic glycolysis and malignant behaviors of GC cells and with a poor prognosis in patients with GC. In vivo experiments have shown that IGF2BP1 knockdown suppresses the carcinogenesis of GC.…”

Effects of N6-methyladenosine modification on metabolic reprogramming in digestive tract tumors

“…In GC cells, AGS and HGC27, METTL3, along with the m6A reader HNRNPA2B1, induces the upregulation of nuclear pre-mRNA domain-containing 1B (RPRD1B) with the assistance of lncRNA NEAT1, thereby activating the c-Jun/c-Fos/AP1 pathway and lipid metabolism [ 102 ]. Moreover, an integrative analysis combining proteomics and m6A microarray data has revealed that METTL3 could enhance apoptosis and caspase activation inhibitor (AVEN) and DnaJ heat shock protein family (Hsp40) member B1 (DNAJB1) levels to strengthen oxidative phosphorylation in GC BGC-823 cells [ 103 ]. METTL3 has also been identified as a key player in enhancing BH4 biosynthesis and advancing GC progression through its impact on elevating m6A modification of pre-B-cell leukemia transcription factor 1 (PBX1) mRNA, thereby enhancing GTP cyclohydrolase 1 (GCH1) expression [ 104 ].…”