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

Nat Commun
Authors
Keywords
Abstract

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.

Year of Publication
2014
Journal
Nat Commun
Volume
5
Pages
3128
Date Published
2014
ISSN
2041-1723
URL
DOI
10.1038/ncomms4128
PubMed ID
24451681
PubMed Central ID
PMC4106362
Links
Grant list
K08 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