Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 21, Pages 5462-5467Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1718338115
Keywords
metabolism; ubiquitin; Fbw7; genomics; informatics
Categories
Funding
- National Cancer Institute Cancer Center [P30CA015704-40, U01CA217862, U54CA209988, R01CA190957, R01 CA193808]
- Turkish Academy of Sciences
- Science Academy of Turkey
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The Fbw7 (F-box/WD repeat-containing protein 7) ubiquitin ligase targetsmultiple oncoproteins for degradation and is commonlymutated in cancers. Like other pleiotropic tumor suppressors, Fbw7's complex biology has impeded our understanding of how Fbw7 mutations promote tumorigenesis and hindered the development of targeted therapies. To address these needs, we employed a transfer learning approach to derive gene-expression signatures from The Cancer Gene Atlas datasets that predict Fbw7 mutational status across tumor types and identified the pathways enriched within these signatures. Genes involved in mitochondrial function were highly enriched in pan-cancer signatures that predict Fbw7 mutations. Studies in isogenic colorectal cancer cell lines that differed in Fbw7 mutational status confirmed that Fbw7 mutations increase mitochondrial gene expression. Surprisingly, Fbw7 mutations shifted cellular metabolism toward oxidative phosphorylation and caused context-specific metabolic vulnerabilities. Our approach revealed unexpected metabolic reprogramming and possible therapeutic targets in Fbw7-mutant cancers and provides a framework to study other complex, oncogenic mutations.
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