TY - JOUR
T1 - Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
AU - Locasale, Jason W.
AU - Grassian, Alexandra R.
AU - Melman, Tamar
AU - Lyssiotis, Costas A.
AU - Mattaini, Katherine R.
AU - Bass, Adam J.
AU - Heffron, Gregory
AU - Metallo, Christian M.
AU - Muranen, Taru
AU - Sharfi, Hadar
AU - Sasaki, Atsuo T.
AU - Anastasiou, Dimitrios
AU - Mullarky, Edouard
AU - Vokes, Natalie I.
AU - Sasaki, Mika
AU - Beroukhim, Rameen
AU - Stephanopoulos, Gregory
AU - Ligon, Azra H.
AU - Meyerson, Matthew
AU - Richardson, Andrea L.
AU - Chin, Lynda
AU - Wagner, Gerhard
AU - Asara, John M.
AU - Brugge, Joan S.
AU - Cantley, Lewis C.
AU - Vander Heiden, Matthew G.
N1 - Funding Information:
Microscopy data for this study were acquired and analyzed in the Nikon Imaging Center at Harvard Medical School. J.W.L. was supported by postdoctoral fellowships from the US National Institutes of Health (NIH) and the American Cancer Society. A.R.G. is a recipient of a National Science Foundation (NSF) Graduate Research Fellowship. L.C.C. and J.S.B. were supported by grants from the NIH and the National Cancer Institute (NCI). M.G.V.H. was supported by grants from the NIH, NCI, Smith Family, Damon Runyon Cancer Research Foundation and the Burroughs Wellcome Fund. We thank N. Vena for technical assistance with the FISH analysis and K. Webster and I. Carrecedo for help with immunohistochemistry. We thank J. Rabinowitz, A. Carrecedo and S.-C. Ng for helpful comments on the manuscript.
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
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U2 - 10.1038/ng.890
DO - 10.1038/ng.890
M3 - Article
C2 - 21804546
AN - SCOPUS:80052258995
SN - 1061-4036
VL - 43
SP - 869
EP - 874
JO - Nature genetics
JF - Nature genetics
IS - 9
ER -