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Role of SF3B1 Mutations in Uveal Melanoma Oncogenesis

Abstract : SF3B1 is the most frequently mutated splicing gene in cancer. SF3B1 mutations are change-of-function missense mutations which lead to the recognition of a cryptic 3’ splice site. The resulting splicing aberrations consist of partial intron retention in the mRNA product, thereby leading to the formation of aberrant transcripts in a set of genes. The functional impact of the aberrant mRNA transcripts remains to be investigated in order to elucidate the oncogenic impact of SF3B1 mutations.Based on an SF3B1 isogenic cell model developed by CRISPR-Degron, we performed a comprehensive molecular study of the transcriptome, synthesis of proteins de novo, protein abundance and translation by RNA-Seq, Click IT, LC-MS/M/S and Polysome Profiling, respectively. Based on the resulting data, we proceeded to examine the metabolic profile of the SF3B1 isogenic cell models.Our results show that mutant SF3B1 does not have a global impact on the RNA nor on protein expression levels, but rather a target-specific impact. Around 35% of the aberrant splicing variants are translated into proteins. We also found that mutant SF3B1 leads to the downregulation of metabolic proteins which in turn leads to a decreased mitochondrial respiration capacity. We revealed that SF3B1mut promotes glycolysis to compensate for their mitochondrial defects, which makes SF3B1mut cells more sensitive to glycolysis inhibition.Here, we provide evidence of the oncogenic role of mutant SF3B1 in uveal melanoma through a metabolic switch towards glycolysis, thus sensitizing cells to glycolysis inhibitors. Overall, our findings elucidate a promising therapeutic strategy for uveal melanoma patients harbouring SF3B1 mutations.
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Submitted on : Saturday, January 1, 2022 - 1:19:07 AM
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Raquel Vivet Noguer. Role of SF3B1 Mutations in Uveal Melanoma Oncogenesis. Human health and pathology. Université Paris sciences et lettres, 2021. English. ⟨NNT : 2021UPSLS059⟩. ⟨tel-03505919⟩

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