目的膀胱癌与苹果酸脱氢酶2(MDH2)的关系尚不清楚,本研究旨在探索MDH2在膀胱癌中的表达以及作用。方法为了揭示MDH2的表达,使用了TCGA(The Cancer Genome Atlas Program)在线数据库分析和实时荧光定量PCR。通过TCGA在线数据库分析评估...目的膀胱癌与苹果酸脱氢酶2(MDH2)的关系尚不清楚,本研究旨在探索MDH2在膀胱癌中的表达以及作用。方法为了揭示MDH2的表达,使用了TCGA(The Cancer Genome Atlas Program)在线数据库分析和实时荧光定量PCR。通过TCGA在线数据库分析评估膀胱癌患者生存期与MDH2表达的关系。然后进行RNA干扰以研究MDH2的表达对膀胱癌的影响,同时通过CCK-8实验分析评估膀胱癌细胞的增殖。结果我们的结果表明,MDH2在膀胱癌组织和膀胱癌细胞系中高表达,且与膀胱癌患者的生存期有关。在膀胱癌细胞中干扰MDH2后其表达明显下调,CCK-8实验表明敲低MDH2表达后抑制了膀胱癌细胞的增值。结论我们的研究表明,MDH2在膀胱癌中高表达且与膀胱癌患者生存期呈负相关,在膀胱癌的发展过程中发挥重要作用,可能成为膀胱癌的潜在诊断标记和治疗靶点。展开更多
Objectives:Breast cancer is characterized by significant metabolic dysregulation,in which altered enzyme activity plays a central role.Malate dehydrogenase 2(MDH2),a key enzyme in the tricarboxylic acid cycle,has been...Objectives:Breast cancer is characterized by significant metabolic dysregulation,in which altered enzyme activity plays a central role.Malate dehydrogenase 2(MDH2),a key enzyme in the tricarboxylic acid cycle,has been implicated in several malignancies,but its role in breast cancer tumorigenesis and progression remains unclear.We aimed to elucidate the oncogenic role of MDH2 in breast cancer and to evaluate its potential as a diagnostic,therapeutic,and prognostic biomarker.Methods:We combined in vitro cell-based assays with mouse xenograft models to systematically dissect how MDH2 governs breast cancer growth.In vitro,we assessed the effects of altered MDH2 expression on proliferation,migration,epithelial–mesenchymal transition(EMT),glucose consumption,and adenosine-5′-triphosphate(ATP)production.In vivo,we dynamically monitored tumor growth driven by MDH2 overexpression.Transcriptomic profiling,untargetedmetabolomics,and in-silico druggability analyses were integrated to elucidate downstream mechanisms and therapeutic potential.Results:In vitro,MDH2 depletion suppressed breast cancer cell proliferation and migration,reversed EMT,and markedly reduced glucose consumption and ATP production.In vivo,MDH2 overexpression accelerated xenograft tumor growth.Transcriptomic profiling revealed MDH2 had modified the gene expression profile of breast cancer cells,affecting several metastasis-related genes.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis identified the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB,also known as AKT)pathway as a downstream effector pathway of MDH2.Untargeted metabolomics uncovered 62 MDH2-regulated metabolites,including the immunomodulatory metabolites adenosine and linoleic acid.In-silico modeling confirmed MDH2 as a novel druggable target.Conclusion:Our findings highlight the role of MDH2 in breast cancer metabolism and suggest it as a promising target for cancer therapies targeting metabolism and tumor growth.展开更多
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 ...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.展开更多
文摘目的膀胱癌与苹果酸脱氢酶2(MDH2)的关系尚不清楚,本研究旨在探索MDH2在膀胱癌中的表达以及作用。方法为了揭示MDH2的表达,使用了TCGA(The Cancer Genome Atlas Program)在线数据库分析和实时荧光定量PCR。通过TCGA在线数据库分析评估膀胱癌患者生存期与MDH2表达的关系。然后进行RNA干扰以研究MDH2的表达对膀胱癌的影响,同时通过CCK-8实验分析评估膀胱癌细胞的增殖。结果我们的结果表明,MDH2在膀胱癌组织和膀胱癌细胞系中高表达,且与膀胱癌患者的生存期有关。在膀胱癌细胞中干扰MDH2后其表达明显下调,CCK-8实验表明敲低MDH2表达后抑制了膀胱癌细胞的增值。结论我们的研究表明,MDH2在膀胱癌中高表达且与膀胱癌患者生存期呈负相关,在膀胱癌的发展过程中发挥重要作用,可能成为膀胱癌的潜在诊断标记和治疗靶点。
基金supported by grants from the GuangDong Basic and Applied Basic Research Foundation(2023B1515130009)the Science and Technology Bureau of Foshan(No.FS0AA-KJ819-4901-0082).
文摘Objectives:Breast cancer is characterized by significant metabolic dysregulation,in which altered enzyme activity plays a central role.Malate dehydrogenase 2(MDH2),a key enzyme in the tricarboxylic acid cycle,has been implicated in several malignancies,but its role in breast cancer tumorigenesis and progression remains unclear.We aimed to elucidate the oncogenic role of MDH2 in breast cancer and to evaluate its potential as a diagnostic,therapeutic,and prognostic biomarker.Methods:We combined in vitro cell-based assays with mouse xenograft models to systematically dissect how MDH2 governs breast cancer growth.In vitro,we assessed the effects of altered MDH2 expression on proliferation,migration,epithelial–mesenchymal transition(EMT),glucose consumption,and adenosine-5′-triphosphate(ATP)production.In vivo,we dynamically monitored tumor growth driven by MDH2 overexpression.Transcriptomic profiling,untargetedmetabolomics,and in-silico druggability analyses were integrated to elucidate downstream mechanisms and therapeutic potential.Results:In vitro,MDH2 depletion suppressed breast cancer cell proliferation and migration,reversed EMT,and markedly reduced glucose consumption and ATP production.In vivo,MDH2 overexpression accelerated xenograft tumor growth.Transcriptomic profiling revealed MDH2 had modified the gene expression profile of breast cancer cells,affecting several metastasis-related genes.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis identified the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB,also known as AKT)pathway as a downstream effector pathway of MDH2.Untargeted metabolomics uncovered 62 MDH2-regulated metabolites,including the immunomodulatory metabolites adenosine and linoleic acid.In-silico modeling confirmed MDH2 as a novel druggable target.Conclusion:Our findings highlight the role of MDH2 in breast cancer metabolism and suggest it as a promising target for cancer therapies targeting metabolism and tumor growth.
基金supported by the National Key Research and Development Program of China (2020YFA0803402 and2019YFA0801703)the National Natural Science Foundation of China(81872240,81802745,81790250/81790253 and 91959202)Innovation Program of Shanghai Municipal Education Commission (N173606)。
文摘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.
