Correction To:Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA

Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-022-01017-8,published online 22 June 2022 In the process of collating the raw data,the authors noticed one inadvertent mistake occurred in Fig.2e that needs to be corrected in the article1.The correct data are provided as follows.The key findings of the article are not affected by the correction.The original article has been corrected.

Acetylation promotes BCAT2 degradation to suppress BCAA catabolism and pancreatic cancer growth

Pancreatic ductal adenocarcinoma(PDAC)is well-known for inefficient early diagnosis,with most patients diagnosed at advanced stages.Increasing evidence indicates that elevated plasma levels of branched-chain amino acids(BCAAs)are associated with an increased risk of pancreatic cancer.Branched-chain amino acid transaminase 2(BCAT2)is an important enzyme in BCAA catabolism that reversibly catalyzes the initial step of BCAA degradation to branched-chain acyl-CoA.Here,we show that BCAT2 is acetylated at lysine 44(K44),an evolutionarily conserved residue.BCAT2 acetylation leads to its degradation through the ubiquitin–proteasome pathway and is stimulated in response to BCAA deprivation.cAMP-responsive element-binding(CREB)-binding protein(CBP)and SIRT4 are the acetyltransferase and deacetylase for BCAT2,respectively.CBP and SIRT4 bind to BCAT2 and control the K44 acetylation level in response to BCAA availability.More importantly,the K44R mutant promotes BCAA catabolism,cell proliferation,and pancreatic tumor growth.Collectively,the data from our study reveal a previously unknown regulatory mechanism of BCAT2 in PDAC and provide a potential therapeutic target for PDAC treatment.

Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth

Epithelial ovarian cancer(EOC) exhibits strong dependency on the tricarboxylic acid(TCA) cycle and oxidative phosphorylation to fuel anabolic process.Here,we show that malate dehydrogenase 2(MDH2),a key enzyme of the TCA cycle,is palmitoylated at cysteine 138(C138) residue,resulting in increased activity of MDH2.We next identify that ZDHHC18 acts as a palmitoyltransferase of MDH2.Glutamine deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and MDH2.MDH2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in vivo.Intriguingly,re-expression of wild-type MDH2,but not its palmitoylation-deficient C138 S mutant,sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer cells.Notably,MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian cancer.These observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer,yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.

Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA

Folic acid,served as dietary supplement,is closely linked to one-carbon metabolism and methionine metabolism.Previous clinical evidence indicated that folic acid supplementation displays dual effect on cancer development,promoting or suppressing tumor formation and progression.However,the underlying mechanism remains to be uncovered.Here,we report that high-folate diet significantly promotes cancer development in mice with hepatocellular carcinoma(HCC)induced by DEN/high-fat diet(HFD),simultaneously with increased expression of methionine adenosyltransferase 2A(gene name,MAT2A;protein name,MATIIα),the key enzyme in methionine metabolism,and acceleration of methionine cycle in cancer tissues.In contrast,folate-free diet reduces MATIIαexpression and impedes HFD-induced HCC development.Notably,methionine metabolism is dynamically reprogrammed with valosin-containing protein p97/p47 complex-interacting protein(VCIP135)which functions as a deubiquitylating enzyme to bind and stabilize MATIIαin response to folic acid signal.Consistently,upregulation of MATIIαexpression is positively correlated with increased VCIP135 protein level in human HCC tissues compared to adjacent tissues.Furthermore,liver-specific knockout of Mat2a remarkably abolishes the advocating effect of folic acid on HFD-induced HCC,demonstrating that the effect of high or free folate-diet on HFD-induced HCC relies on Mat2a.Moreover,folate and multiple intermediate metabolites in one-carbon metabolism are significantly decreased in vivo and in vitro upon Mat2a deletion.Together,folate promotes the integration of methionine and one-carbon metabolism,contributing to HCC development via hijacking MATIIαmetabolic pathway.This study provides insight into folate-promoted cancer development,strongly recommending the tailor-made folate supplement guideline for both sub-healthy populations and patients with cancer expressing high level of MATIIαexpression.