摘要
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.
基金
the generous providing the plasmid of VCIP135-S1207A from Dr.Zhen-Kun Lou’s lab.27 We also appreciate the Biomedical Core Facility of Fudan University for technical support
supported by National Key R&D Program of China(2020YFA0803402 and 2019YFA0801703 to Q.-Y.L.)
National Natural Science Foundation of China(Nos.81790250/81790253,91959202 and 82121004 to Q.-Y.L.,No.81872240 to M.Y.,No.82002951 to J.-T.L.
Innovation Program of Shanghai Municipal Education Commission(No.N173606 to Q.-Y.L.).