Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate

Jing Fan, Xin Teng, Ling Liu, Katherine R. Mattaini, Ryan E. Looper, Matthew G. Vander Heiden, Joshua D. Rabinowitz

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Human D-3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in the serine biosynthetic pathway, is genomically amplified in tumors including breast cancer and melanoma. In PHGDH-amplified cancer cells, knockdown of PHGDH is not fully rescued by exogenous serine, suggesting possible additional growth-promoting roles for the enzyme. Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of α-ketoglutarate (AKG) to the oncometabolite D-2-hydroxyglutarate (D-2HG). Knockdown of PHGDH decreased cellular 2HG by approximately 50% in the PHGDH-amplified breast cancer cell lines MDA-MB-468 (normal concentration 93 μM) and BT-20 (normal concentration 35 μM) and overexpression of PHGDH increased cellular 2HG by over 2-fold in non-PHGDH-amplified MDA-MB-231 breast cancer cells, which normally display very low PHGDH expression. The reduced 2HG level in PHGDH knockdown cell lines can be rescued by PHGDH re-expression, but not by a catalytically inactive PHGDH mutant. The initial connection between cancer and D-2HG involved production of high levels of D-2HG by mutant isocitrate dehydrogenase. More recently, however, elevated D-2HG has been observed in breast cancer tumors without isocitrate dehydrogenase mutation. Our results suggest that PHGDH is one source of this D-2HG.

Original languageEnglish (US)
Pages (from-to)510-516
Number of pages7
JournalACS chemical biology
Volume10
Issue number2
DOIs
StatePublished - Feb 20 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

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    Fan, J., Teng, X., Liu, L., Mattaini, K. R., Looper, R. E., Vander Heiden, M. G., & Rabinowitz, J. D. (2015). Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate. ACS chemical biology, 10(2), 510-516. https://doi.org/10.1021/cb500683c