Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis

Jason W. Locasale, Alexandra R. Grassian, Tamar Melman, Costas A. Lyssiotis, Katherine R. Mattaini, Adam J. Bass, Gregory Heffron, Christian M. Metallo, Taru Muranen, Hadar Sharfi, Atsuo T. Sasaki, Dimitrios Anastasiou, Edouard Mullarky, Natalie I. Vokes, Mika Sasaki, Rameen Beroukhim, Gregory Stephanopoulos, Azra H. Ligon, Matthew Meyerson, Andrea L. RichardsonLynda Chin, Gerhard Wagner, John M. Asara, Joan S. Brugge, Lewis C. Cantley, Matthew G. Vander Heiden

Research output: Contribution to journalArticlepeer-review

673 Scopus citations


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. 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.

Original languageEnglish (US)
Pages (from-to)869-874
Number of pages6
JournalNature genetics
Issue number9
StatePublished - Sep 2011
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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