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

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.