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Nat Commun DOI:10.1038/ncomms4128

Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer.

Publication TypeJournal Article
Year of Publication2014
AuthorsNilsson, R, Jain, M, Madhusudhan, N, Sheppard, NGustafsson, Strittmatter, L, Kampf, C, Huang, J, Asplund, A, Mootha, VK
JournalNat Commun
Date Published2014
KeywordsAminohydrolases, Cell Death, Cell Line, Transformed, Cell Proliferation, Folic Acid, Gene Expression Regulation, Neoplastic, Humans, Metabolic Networks and Pathways, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, Multienzyme Complexes, Neoplasms, RNA Interference, RNA, Messenger

Metabolic remodeling is now widely regarded as a hallmark of cancer, but it is not clear whether individual metabolic strategies are frequently exploited by many tumours. Here we compare messenger RNA profiles of 1,454 metabolic enzymes across 1,981 tumours spanning 19 cancer types to identify enzymes that are consistently differentially expressed. Our meta-analysis recovers established targets of some of the most widely used chemotherapeutics, including dihydrofolate reductase, thymidylate synthase and ribonucleotide reductase, while also spotlighting new enzymes, such as the mitochondrial proline biosynthetic enzyme PYCR1. The highest scoring pathway is mitochondrial one-carbon metabolism and is centred on MTHFD2. MTHFD2 RNA and protein are markedly elevated in many cancers and correlated with poor survival in breast cancer. MTHFD2 is expressed in the developing embryo, but is absent in most healthy adult tissues, even those that are proliferating. Our study highlights the importance of mitochondrial compartmentalization of one-carbon metabolism in cancer and raises important therapeutic hypotheses.


Alternate JournalNat Commun
PubMed ID24451681
PubMed Central IDPMC4106362
Grant ListK08 HL107451 / HL / NHLBI NIH HHS / United States
R01 DK081457 / DK / NIDDK NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
NIH K08HL107451 / HL / NHLBI NIH HHS / United States
R01DK081457 / DK / NIDDK NIH HHS / United States