Glycolysis Dependency as a Hallmark of <i>SF3B1</i>-Mutated Cells
<i>SF3B1</i> 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 alt...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/9/2113 |
| _version_ | 1797505457294671872 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Raquel Vivet-Noguer |
| collection | DOAJ |
| description | <i>SF3B1</i> 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. |
| first_indexed | 2024-03-10T04:18:51Z |
| format | Article |
| id | doaj.art-49ba226930084578a17a67a7149e054c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:18:51Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-49ba226930084578a17a67a7149e054c2023-11-23T07:55:01ZengMDPI AGCancers2072-66942022-04-01149211310.3390/cancers14092113Glycolysis Dependency as a Hallmark of <i>SF3B1</i>-Mutated CellsRaquel Vivet-Noguer0Malcy Tarin1Christine Canbezdi2Stephane Dayot3Lisseth Silva4Alexandre Houy5Sylvain Martineau6Virginie Mieulet7Géraldine Gentric8Damarys Loew9Bérangère Lombard10Fariba Nemati11Sophie Richon12Lea Guyonnet13Vincent Servois14Stephan Vagner15Marc-Henri Stern16Sergio Roman-Roman17Samar Alsafadi18Translational Research Department, Institut Curie, PSL Research University, 75248 Paris, FranceTranslational Research Department, Institut Curie, PSL Research University, 75248 Paris, FranceTranslational Research Department, Institut Curie, PSL Research University, 75248 Paris, FranceINSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale Contre le Cancer, Institut Curie, PSL Research University, 75248 Paris, FranceTranslational Research Department, Institut Curie, PSL Research University, 75248 Paris, FranceINSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale Contre le Cancer, Institut Curie, PSL Research University, 75248 Paris, FranceCNRS UMR3348, INSERM U1278, Institut Curie, PSL Research University, 75248 Paris, FranceINSERM U830, Stress and Cancer Laboratory, Equipe labellisée par la Ligue Nationale Contre le Cancer, Institut Curie, PSL Research University, 75248 Paris, FranceINSERM U830, Stress and Cancer Laboratory, Equipe labellisée par la Ligue Nationale Contre le Cancer, Institut Curie, PSL Research University, 75248 Paris, FranceMass Spectrometry and Proteomics Facility, Institut Curie, PSL Research University, 75248 Paris, FranceMass Spectrometry and Proteomics Facility, Institut Curie, PSL Research University, 75248 Paris, FranceTranslational Research Department, Institut Curie, PSL Research University, 75248 Paris, FranceCNRS UMR 144, Institut Curie, PSL Research University, 75248 Paris, FranceCytometry Core, Institut Curie, PSL Research University, 75248 Paris, FranceDepartment of Radiology, Institut Curie, PSL Research University, 75248 Paris, FranceCNRS UMR3348, INSERM U1278, Institut Curie, PSL Research University, 75248 Paris, FranceINSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale Contre le Cancer, Institut Curie, PSL Research University, 75248 Paris, FranceTranslational Research Department, Institut Curie, PSL Research University, 75248 Paris, FranceTranslational Research Department, Institut Curie, PSL Research University, 75248 Paris, France<i>SF3B1</i> 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.https://www.mdpi.com/2072-6694/14/9/2113glycolysismetabolismSF3B1splicinguveal melanoma |
| spellingShingle | 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 Glycolysis Dependency as a Hallmark of <i>SF3B1</i>-Mutated Cells Cancers glycolysis metabolism SF3B1 splicing uveal melanoma |
| title | Glycolysis Dependency as a Hallmark of <i>SF3B1</i>-Mutated Cells |
| title_full | Glycolysis Dependency as a Hallmark of <i>SF3B1</i>-Mutated Cells |
| title_fullStr | Glycolysis Dependency as a Hallmark of <i>SF3B1</i>-Mutated Cells |
| title_full_unstemmed | Glycolysis Dependency as a Hallmark of <i>SF3B1</i>-Mutated Cells |
| title_short | Glycolysis Dependency as a Hallmark of <i>SF3B1</i>-Mutated Cells |
| title_sort | glycolysis dependency as a hallmark of i sf3b1 i mutated cells |
| topic | glycolysis metabolism SF3B1 splicing uveal melanoma |
| url | https://www.mdpi.com/2072-6694/14/9/2113 |
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