More than a metabolic enzyme: MTHFD2 as a novel target for anticancer therapy?
Open accessAbstract
The bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a mitochondrial one-carbon folate metabolic enzyme whose role in cancer was not known until recently. MTHFD2 is highly expressed in embryos and a wide range of tumors but has low or absent expression in most adult differentiated tissues. Elevated MTHFD2 expression is associated with poor prognosis in both hematological and solid malignancy. Its depletion leads to suppression of multiple malignant phenotypes including proliferation, invasion, migration, and induction of cancer cell death. The non-metabolic functions of this enzyme, especially in cancers, have thus generated considerable research interests. This review summarizes current knowledge on both the metabolic functions and non-enzymatic roles of MTHFD2. Its expression, potential functions, and regulatory mechanism in cancers are highlighted. The development of MTHFD2 inhibitors and their implications in pre-clinical models are also discussed.
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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 [7]
Overexpression of MTHFD2 is associated with poor prognosis and clinicopathological parameters in breast, renal, liver, pancreatic, and colorectal cancers and some brain cancers.
“Overexpression of MTHFD2 is associated with poor prognosis and clinicopathological parameters in breast, renal, liver, pancreatic, and colorectal cancers and some brain cancers.7”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [7]
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One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration
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A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight
Cuthbertson, C. R., Arabzada, Z., Bankhead, A., Kyani, A., & Neamati, N. (2021) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.0c00223 · Cited by 57 · see citing works
- Authors
- Zhu, Z., & Leung, G. K. K.
- Affiliations
- University of Hong Kong (HK)
- ORCID
- Zhu, Zhiyuan
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2020-04-28
- Volume
- 10
- Pages
- 658-658
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC7199629
- OpenAlex
- W3022898307
- Cited by
- 106
- References
- 58
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 26 · 2023: 17 · 2022: 17 · 2021: 17
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- MTHFD2, cancer metabolism, non-enzymatic function, anticancer drug targets, cancer prognosis, cancer cell proliferation and invasion, cancer cell death
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