Deactivation of the mitochondrial pyruvate dehydrogenase complex(PDC)is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis.Studies examining PDC activity regulati...Deactivation of the mitochondrial pyruvate dehydrogenase complex(PDC)is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis.Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase(E1),leaving other post-translational modifications largely unexplored.Here,we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X(PDHX)commonly occurs in hepatocellular carcinoma,disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression.PDHX,an E3-binding protein in the PDC,is acetylated by the p300 at Lys 488,impeding the interaction between PDHX and dihydrolipoyl transacetylase(E2),thereby disrupting PDC assembly to inhibit its activation.PDC disruption results in the conversion of most glucose to lactate,contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression,facilitating tumor progression.These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity,linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.展开更多
基金supported in part by National Natural Science Foundation of China(Grant Nos.81930083,82192893,81821001,and 82303217)National Key R&D Program of China(2022YFA1304504)+2 种基金the Chinese Academy of Sciences(XDB39000000)the Global Select Project(DJK-LX-2022001)of the Institute of Health and Medicine,Hefei Comprehensive National Science Centerthe Fundamental Research Funds for the Central Universities(WK9100000051).
文摘Deactivation of the mitochondrial pyruvate dehydrogenase complex(PDC)is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis.Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase(E1),leaving other post-translational modifications largely unexplored.Here,we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X(PDHX)commonly occurs in hepatocellular carcinoma,disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression.PDHX,an E3-binding protein in the PDC,is acetylated by the p300 at Lys 488,impeding the interaction between PDHX and dihydrolipoyl transacetylase(E2),thereby disrupting PDC assembly to inhibit its activation.PDC disruption results in the conversion of most glucose to lactate,contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression,facilitating tumor progression.These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity,linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.
