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.