Glycolysis Dependency as a Hallmark of SF3B1-Mutated Cells

Simple Summary Cancer-associated SF3B1 mutations result in aberrant transcripts whose fate remains unknown. We aimed to investigate the functional consequences of these splice aberrations. Our results show that SF3B1 mutation alters the translation of transcripts encoding proteins involved in metabolism, which triggers a metabolic switch toward an increased glucose uptake. Consequently, SF3B1-mutated cells are more sensitive to glycolysis inhibition than SF3B1 wild-type cells. SF3B1 mutations are recurrent in cancer and result in aberrant splicing of a previously defined set of genes. Here, we investigated the fate of aberrant transcripts induced by mutant SF3B1 and the related functional consequences. We first demonstrate that mutant SF3B1 does not alter global nascent protein synthesis, suggesting target-dependent consequences. Polysome profiling revealed that 35% of aberrantly spliced transcripts are more translated than their corresponding canonically spliced transcripts. This mostly occurs in genes with enriched metabolic functions. Furthermore, LC-MS/MS analysis showed that mutant SF3B1 impacts the abundance of proteins involved in metabolism. Functional metabolic characterization revealed that mutant SF3B1 decreases mitochondrial respiration and promotes glycolysis to compensate for defective mitochondrial metabolism. Hence, mutant SF3B1 induces glycolysis dependency, which sensitizes cells to glycolysis inhibition. Overall, we provide evidence of the oncogenic involvement of mutant SF3B1 in uveal melanoma through a metabolic switch to glycolysis, revealing vulnerability to glycolysis inhibitors as a promising therapeutic strategy.