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Pan-cancer transcriptional signatures predictive of oncogenic mutations reveal that Fbw7 regulates cancer cell oxidative metabolism. | LitMetric

AI Article Synopsis

  • Fbw7 is a protein that helps regulate oncoproteins by marking them for degradation and is often mutated in various cancers, complicating treatment development.
  • Researchers used a transfer learning method to analyze gene expression data to predict Fbw7 mutation status across different cancers and found that genes related to mitochondrial function were notably involved.
  • The study showed that Fbw7 mutations not only increased mitochondrial gene expression but also altered cellular metabolism, unveiling potential new treatment targets for cancers with Fbw7 mutations.

Article Abstract

The Fbw7 (F-box/WD repeat-containing protein 7) ubiquitin ligase targets multiple oncoproteins for degradation and is commonly mutated 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003503PMC
http://dx.doi.org/10.1073/pnas.1718338115DOI Listing

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