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Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism
Fan Zhang1,2 , Di Wang1,2 , Jintao Li1,2 , Ying Su1,2 , Suling Liu1,2 , Qun-Ying Lei1,2,3 , Miao Yin1,2,*
1Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences & School of Basic Medical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, Shanghai Key Laboratory of Radiation Oncology, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai 200032, China
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
3State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China
*Correspondence to:Miao Yin ,
J Mol Cell Biol, Volume 14, Issue 4, April 2022, mjac020,
Keyword: folate metabolism, MTHFD2, CUL3, SIRT4, acetylation, breast cancer

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.