Glycolysis Dependency as a Hallmark of SF3B1-Mutated Cells

Nom de la revue
Raquel Vivet-Noguer, Malcy Tarin, Christine Canbezdi, Stephane Dayot, Lisseth Silva, Alexandre Houy, Sylvain Martineau, Virginie Mieulet, Géraldine Gentric, Damarys Loew, Bérangère Lombard, Fariba Nemati, Sophie Richon, Lea Guyonnet, Vincent Servois, Stephan Vagner, Marc-Henri Stern, Sergio Roman-Roman, Samar Alsafadi

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.