PDHX acetylation facilitates tumor progression by disrupting PDC assembly and activating lactylation-mediated gene expression.

Zetan JIANG; Nanchi XIONG; Ronghui YAN; Shi-Ting LI; Haiying LIU; Qiankun MAO; Yuchen SUN; Shengqi SHEN; Ling YE; Ping GAO; Pinggen ZHANG; Weidong JIA; Huafeng ZHANG

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PDHX acetylation facilitates tumor progression by disrupting PDC assembly and activating lactylation-mediated gene expression.

Author: Zetan JIANG ¹ ; Nanchi XIONG ¹ ; Ronghui YAN ¹ ; Shi-Ting LI ² ; Haiying LIU ¹ ; Qiankun MAO ³ ; Yuchen SUN ³ ; Shengqi SHEN ² ; Ling YE ³ ; Ping GAO ² ; Pinggen ZHANG ¹ ; Weidong JIA ¹ ; Huafeng ZHANG ¹
Author Information

1. Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.
2. Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China.
3. The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.
Publication Type:Journal Article
Keywords: PDC; PDHX; acetylation; lactylation; liver cancer
MeSH: 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
From: Protein & Cell 2025;16(1):49-63
CountryChina
Language:English
Abstract: 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.