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.
Humans ; Acetylation ; Carcinoma, Hepatocellular/genetics* ; Liver Neoplasms/genetics* ; Pyruvate Dehydrogenase Complex/genetics* ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Cell Line, Tumor ; Protein Processing, Post-Translational ; Histones/metabolism* ; Disease Progression

Objective To evaluate the apphcation value of peripheral blood neutrophil CD64 expression in early differential diagnosis of etiology in children with community-acquired pneumonia.Methods From June 2014 to June 2015 in our hospital,total of 99 cases of different pathogen infection were divided into three groups,bacterial pneumonia group (n =41),non-bacterial pneumonia group(n =38),healthy children group (n =20);and the non-bacterial pneumonia group was divided into two subgroups,viral pneumonia group (n =22) and mycoplasma pneumoniae pneumonia group(n =16).Flow cytometry was used to test the median fluorescence intensity (MFI) of peripheral blood neutrophil CD64.The levels of peripheral blood CRP,WBC and neutrophil percentage were detected.Results The levels of CD64 expression,CRP and WBC in bacterial pneumonia group were statistically higher than those of non-bacterial pneumonia group and healthy children group respectively (both P ＜ 0.01).The optimal cutoff value of CD64 was 6 519 MFI when using ROC curve,and the sensitivity and specificity of the diagnosis of bacterial pneumonia were 87.8％ and 89.7％ respectively.The levels of CD64 expression in bacterial pneumonia group were significantly higher than those in viral pneumonia group,mycoplasma pneumoniae pneumonia group and healthy children group (all P ＜ 0.01).Conclusion The expression of peripheral blood neutrophil CD64 increases in children with community-acquired pneumonia of bacteria infection.It can be used to guide early diagnosis of children with bacterial pneumonia and the using of antibiotics.