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METTL3-dependent m6A RNA Modifications Orchestrate the HNF1B-associated Redox and the Metabolic Vulnerability in Cancer [MeRIP-seq]

ABSTRACT: Internal RNA modifications, such as N6-methyladenosine (m6A), are widespread in mammalian cells but their importance in cancer metabolism remains poorly understood. Here, we demonstrate that the m6A methyltransferase complex, composed of METTL3 and METTL14, is a critical regulator of the metabolic dependencies in human cancers. Inhibiting METTL3-mediated m6A modifications, both genetically and chemically, significantly impairs the antioxidant capacity of pancreatic cancer cells, sensitizing them to the oxidative stress. We found that m6A modifications at the 3'-untranslated regions (3'-UTRs) of the HNF1B mRNA enhances its stability and expression levels. Furthermore, the loss of HNF1B triggers oxidative stress-induced cell death across multiple cancer types, recapitulating the metabolic dysfunction caused by m6A depletion and revealing HNF1B as a key mediator of the glutathione metabolic program. By establishing a link between m6A modifications and cellular antioxidant responses via HNF1B, our findings suggest that METTL3 is a metabolic vulnerability in cancer and highlight its potential as a therapeutic target for m6A-directed therapies in cancer.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE286385 | GEO | 2026/01/01

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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METTL3-dependent m6A RNA Modifications Orchestrate the HNF1B-associated Redox and the Metabolic Vulnerability in Cancer [MeRIP-seq]

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