Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
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PHGDH_NatGen_FINAL2.0.pdf
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5.95 MB
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Author(s)
Locasale, Jason W.
Grassian, Alexandra R.
Melman, Tamar
Lyssiotis, Costas A.
Mattaini, Katherine Ruth
Bass, Adam J.
Heffron, Gregory J.
Metallo, Christian M.
Muranen, Taru
Sharfi, Hadar
Date Issued
July 2011
Journal
Nature Genetics
Publisher
Nature Publishing Group
Citation
Locasale, Jason W et al. “Phosphoglycerate Dehydrogenase Diverts Glycolytic Flux and Contributes to Oncogenesis.” Nature Genetics 43.9 (2011): 869–874.
Version
Author's final manuscript
Abstract
Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood [1, 2]. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike 3.0
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DOI of Published Version
https://doi.org/10.1038/ng.890
