Abstract
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.
Highlights
MTHFD2 (350 amino acids, 37kDa) is one of the major enzymes involved in mitochondrial folate one-carbon metabolism and is known as NMDMC (NAD-dependent mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase)
Highly expressed MTHFD2 is associated with poor disease outcomes in breast cancer [2], colorectal cancer (CRC) [3], renal cell carcinoma (RCC) [4], and hepatocellular carcinoma (HCC) [5]; upregulation of MTHFD2 may contribute to an increased risk of bladder cancer [6]
MTHFD2 was upregulated in glioma [20] and positively correlated with tumor grade [21]
Summary
MTHFD2 (350 amino acids, 37kDa) is one of the major enzymes involved in mitochondrial folate one-carbon metabolism and is known as NMDMC (NAD-dependent mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase). Despite its well-known bifunctional dehydrogenase and cyclohydrolase activities, MTHFD2 has been reported to be required for cancer proliferation and may have profound role in tumor development and progression. This metabolic enzyme has attracted particular interests in cancer research for several reasons. MTHFD2 is upregulated in various cancers, transformed cells, and developing embryos, but has low or undetectable level in most differentiated normal adult tissues [1]. MTHFD2 is oncogenic in nature and may serve as a prognostic indicator as well as a therapeutic target in cancers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
