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 (PDH, E1), leaving other post-translational modifications (PTMs) largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma (HCC), disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein (E3BP) in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (DLAT, 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 HCC progression and providing a potential biomarker and therapeutic target for further development.

中文翻译：

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PDHX 乙酰化通过破坏 PDC 组装和激活乳酰化介导的基因表达来促进肿瘤进展。


线粒体丙酮酸脱氢酶复合物（PDC）的失活对于癌细胞从氧化磷酸化到有氧糖酵解的代谢转换非常重要。检查 PDC 活性调节的研究主要集中在丙酮酸脱氢酶 (PDH、E1) 的磷酸化上，而其他翻译后修饰 (PTM) 很大程度上尚未探索。在这里，我们证明丙酮酸脱氢酶复合体成分 X (PDHX) 的 Lys 488 乙酰化通常发生在肝细胞癌 (HCC) 中，破坏 PDC 组装并有助于乳酸驱动的基因表达的表观遗传控制。 PDHX 是 PDC 中的一种 E3 结合蛋白 (E3BP)，被 p300 第 488 位赖氨酸乙酰化，阻碍 PDHX 与二氢硫辛酰转乙酰酶 (DLAT、E2) 之间的相互作用，从而破坏 PDC 组装以抑制其激活。 PDC 破坏导致大部分葡萄糖转化为乳酸，促进有氧糖酵解和 H3K56 乳酰化介导的基因表达，促进肿瘤进展。这些发现强调了 PDHX 乙酰化在调节 PDC 组装和活性中的先前未被认识的作用，在 HCC 进展过程中将 PDHX Lys 488 乙酰化和组蛋白乳酰化联系起来，并为进一步开发提供了潜在的生物标志物和治疗靶点。