ArticleJournal of molecular cell biology2022
Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism.
Article in Journal of molecular cell biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- MTHFD2: a promising metabolic checkpoint for diseases.Journal of translational medicine · 2026Review
- SIRT4 regulates antiviral and autoimmune responses by promoting cGAS-mediated signaling pathways.EMBO reports · 2026Article
- Sirtuin 4 Knockout Aggravates Sepsis-Induced Acute Liver Injury by Enhancing Mitochondrial Fission and Mitophagy in Hepatocytes.Mediators of inflammation · 2026Article
- Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling.Nature communications · 2025Article
- The advances in acetylation modification in senescence and aging-related diseases.Frontiers in physiology · 2025Review
- SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling.Life science alliance · 2024Article
- Targeting SHMTs and MTHFDs in cancer: attractive opportunity for anti-tumor strategy.Frontiers in pharmacology · 2024Review
- Targeting sirtuins for cancer therapy: epigenetics modifications and beyond.Theranostics · 2024Review
- Regulatory mechanisms of one-carbon metabolism enzymes.The Journal of biological chemistry · 2023Review
- Article
- SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis.Cell death and differentiation · 2023Article
- Review
- COVID-19 metabolism: Mechanisms and therapeutic targets.MedComm · 2022Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Folate metabolism plays an essential role in tumor development. Various cancers display therapeutic response to reagents targeting key enzymes of the folate cycle, but obtain chemoresistance later. Therefore, novel targets in folate metabolism are highly demanded. Methylenetetrahydrofolate dehydrogenase/methylenetetrahydrofolate cyclohydrolase 2 (MTHFD2) is one of the key enzymes in folate metabolism and its expression is highly increased in multiple human cancers. However, the underlying mechanism that regulates MTHFD2 expression remains unknown. Here, we elucidate that SIRT4 deacetylates the conserved lysine 50 (K50) residue in MTHFD2. K50 deacetylation destabilizes MTHFD2 by elevating cullin 3 E3 ligase-mediated proteasomal degradation in response to stressful stimuli of folate deprivation, leading to suppression of nicotinamide adenine dinucleotide phosphate production in tumor cells and accumulation of intracellular reactive oxygen species, which in turn inhibits the growth of breast cancer cells. Collectively, our study reveals that SIRT4 senses folate availability to control MTHFD2 K50 acetylation and its protein stability, bridging nutrient/folate stress and cellular redox to act on cancer cell growth.
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