Glycolysis Dependency as a Hallmark of SF3B1-Mutated Cells

Area of Science:

• Molecular Biology
• Cancer Biology
• Metabolomics

Background:

• Mutations in SF3B1 are common in cancers, leading to abnormal gene splicing.
• The functional consequences of SF3B1 mutations on transcript fate and cellular metabolism are not fully understood.

Purpose of the Study:

• To investigate the impact of mutant SF3B1 on aberrant transcript translation and protein abundance.
• To determine the functional metabolic consequences of SF3B1 mutations in cancer.
• To explore therapeutic strategies targeting metabolic alterations induced by mutant SF3B1.

Main Methods:

• Polysome profiling to assess mRNA translation.
• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) for protein abundance analysis.
• Functional metabolic assays including mitochondrial respiration and glycolysis measurements.

Main Results:

• Mutant SF3B1 leads to increased translation of a subset of aberrantly spliced transcripts, particularly those involved in metabolism.
• SF3B1 mutations alter protein abundance in metabolic pathways.
• Cells with mutant SF3B1 exhibit decreased mitochondrial respiration and increased glycolysis, creating a dependency on glycolysis.
• This dependency sensitizes cancer cells to glycolysis inhibitors.

Conclusions:

• Mutant SF3B1 promotes oncogenesis in uveal melanoma via a metabolic switch to glycolysis.
• Targeting glycolysis represents a promising therapeutic approach for cancers with SF3B1 mutations.