Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer
Open accessAbstract
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.
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MTHFD2 is among the top three most frequently overexpressed metabolic enzymes in cancer.
“methylene tetrahydrofolate dehydrogenase 2 (MTHFD2), a component of the mitochondrial arm of the one-carbon pathway, was found to be among the top three most frequently overexpressed metabolic enzymes in cancer”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Nilsson et al., 2014
Meta-analysis identified PYCR1 as one of the most commonly overexpressed genes in tumors.
“In fact, a meta-analysis of metabolic enzyme expression across diverse tumor types identified PYCR1 as one of the most commonly overexpressed genes in tumors (Nilsson et al., 2014).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Nilsson et al., 2014
The mitochondrial isoforms of SHMT and MTHFD, SHMT2 and MTHFD2, are clinically relevant in the context of cancer.
“Literature continues to suggest that the mitochondrial isoforms of these enzymes are clinically relevant in the context of cancer.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [9]
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- Authors
- Nilsson, R., Jain, M., Madhusudhan, N., Sheppard, N. G., Strittmatter, L., Kampf, C., Huang, J., Asplund, A., & Mootha, V. K.
- Affiliations
- Karolinska Institutet (SE)
- Broad Institute (US)
- Uppsala University (SE)
- La Jolla Institute for Immunology (US)
- Corresponding author
- Nilsson, Roland
- Mootha, Vamsi K.
- Venue
- Nature Communications
- Published
- 2014-01-23
- Volume
- 5
- Issue
- 1
- Pages
- 3128-3128
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4106362
- OpenAlex
- W2168735777
- Cited by
- 607
- References
- 47
- Citations by year
- 2026: 37 · 2025: 49 · 2024: 61 · 2023: 77 · 2022: 57 · 2021: 73 · 2020: 61 · 2019: 53 · 2018: 32 · 2017: 30 · 2016: 44 · 2015: 17 · 2014: 16
- FWCI
- 11.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Vetenskapsrådet
- National Institutes of Health
- National Heart, Lung, and Blood Institute (K08HL107451, NIH K08HL107451)
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK081457)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- MTHFD2, one-carbon metabolism, cancer metabolism, breast cancer survival, PYCR1, proline biosynthesis, dihydrofolate reductase, thymidylate synthase, ribonucleotide reductase, chemotherapeutic target, mitochondrial compartmentalization
- MeSH terms
- Aminohydrolases, Cell Line, Transformed, Folic Acid, Humans, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, Multienzyme Complexes, Neoplasms, RNA, Messenger, Gene Expression Regulation, Neoplastic, Cell Death, RNA Interference, Cell Proliferation, Metabolic Networks and Pathways
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