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

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.

Keywords

acetylation / lactylation / liver cancer / PDC / PDHX

References

[1] An S, Yao Y, Hu H et al. PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via FiS1 lactylation. Cell Death Dis 2023;14:457.

[2] Bian XL, Chen HZ, Yang PB et al. Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carb oxykinase sumoylation. Nat Commun 2017;8:14420.

[3] Cai Z, Li CF, Han F et al. Phosphorylation of PDHA by AMPK drives TCA cycle to promote cancer metastasis. Mol Cell 2020;80:263–278.e7 e267.

[4] Certo M, Tsai CH, Pucino V et al. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol 2021;21:151–161.

[5] Chen Y, Wu J, Zhai L et al. Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell 2024;187:294–311.e21.

[6] DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab 2020;2:127–129.

[7] Depianto D, Kerns ML, Dlugosz AA et al. Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin. Nat Genet 2010;42:910–914.

[8] Eastlack SC, Dong S, Ivan C et al. Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer. Mol Cancer 2018;17:100.

[9] Fan J, Shan C, Kang HB et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 2014;53:534–548.

[10] Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Science 2020;368:152–162.

[11] Feng J, Li J, Wu L et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res 2020;39:126.

[12] Gao Y, Nihira NT, Bu X et al. Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy. Nat Cell Biol 2020;22:1064–1075.

[13] Guertin DA, Wellen KE. Acetyl-CoA metabolism in cancer. Nat Rev Cancer 2023;23:156–172.

[14] Han Y, Zhang YY, Pan YQ et al. IL-1beta-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance. Mol Cell 2023;83:1887–1902.e8 e1888.

[15] Haugrud AB, Zhuang Y, Coppock JD et al. Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells. Breast Cancer Res Treat 2014;147:539–550.

[16] Hiromasa Y, Fujisawa T, Aso Y et al. Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by e2 and e2 plus the e3-binding protein and their capacities to bind the e1 and e3 components. J Biol Chem 2004;279:6921–6933.

[17] Hou F, Shi DB, Guo XY et al. HRCT1, negatively regulated by miR-124-3p, promotes tumor metastasis and the growth of gastric cancer by activating the ERBB2-MAPK pathway. Gastric Cancer 2023;26:250–263.

[18] Huang J, Dai W, Xiao D et al. Acetylation-dependent SAGA complex dimerization promotes nucleosome acetylation and gene transcription. Nat Struct Mol Biol 2022;29:261–273.

[19] Hui S, Ghergurovich JM, Morscher RJ et al. Glucose feeds the TCA cycle via circulating lactate. Nature 2017;551:115–118.

[20] Kim JW, Tchernyshyov I, Semenza GL et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006;3:177–185.

[21] Kumagai S, Koyama S, Itahashi K et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022;40:201–218. e9 e209.

[22] Lei MZ, Li XX, Zhang Y et al. Acetylation promotes BCAT2 degradation to suppress BCAA catabolism and pancreatic cancer growth. Signal Transduct Target Ther 2020;5:70.

[23] Li M, Luo RZ, Chen JW et al. High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma. J Transl Med 2011;9:5.

[24] Li ST, Huang D, Shen SQ et al. Myc-mediated SDHA acetylation triggers epigenetic regulation of gene expression and tumorigenesis. Nat Metab 2020;2:256–269.

[25] Li YP, He XN, Lu X et al. METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions. Nat Commun 2022;13:6350.

[26] Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 2016;41:211–218.

[27] Liu X, Wang L, Zhao K et al. The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 2008;451:846–850.

[28] Lv L, Li D, Zhao D et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell 2011;42:719–730.

[29] Ma X, Li C, Sun L et al. LiN28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1. Nat Commun 2014;5:5212.

[30] Mullen AR, DeBerardinis RJ. Genetically-defined metabolic reprogramming in cancer. Trends Endocrinol Metab 2012;23:552–559.

[31] Narita T, Weinert BT, Choudhary C. Functions and mechanisms of non-histone protein acetylation. Nat Rev Mol Cell Biol 2019;20:156–174.

[32] Nie H, Ju H, Fan J et al. O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth. Nat Commun 2020;11:36.

[33] Papandreou I, Cairns RA, Fontana L et al. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006;3:187–197.

[34] Park S, Jeon JH, Min BK et al. Role of the pyruvate dehydrogenase complex in metabolic remodeling: differential pyruvate dehydrogenase complex functions in metabolism. Diabetes Metab J 2018;42:270–281.

[35] Patel MS, Korotchkina LG. Regulation of mammalian pyruvate dehydrogenase complex by phosphorylation: complexity of multiple phosphorylation sites and kinases. Exp Mol Med 2001;33:191–197.

[36] Patel MS, Nemeria NS, Furey W et al. The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem 2014;289:16615–16623.

[37] Pavlova NN, Zhu JJ, Thompson CB. The hallmarks of cancer metabolism: still emerging. Cell Metab 2022;34:355–377.

[38] Prajapati S, Haselbach D, Wittig S et al. Structural and functional analyses of the human PDH complex suggest a “Division-of-Labor” mechanism by local E1 and E3 clusters. Structure 2019;27:1124–1136.e4.

[39] Rho H, Terry AR, Chronis C et al. Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis. Cell Metab 2023;35:1406–1423.e8.

[40] Shen H, Decollogne S, Dilda PJ et al. Dual-targeting of aberrant glucose metabolism in glioblastoma. J Exp Clin Cancer Res 2015;34:14.

[41] Shvedunova M, Akhtar A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat Rev Mol Cell Biol 2022;23:329–349.

[42] Smolle M, Prior AE, Brown AE et al. A new level of architectural complexity in the human pyruvate dehydrogenase complex. J Biol Chem 2006;281:19772–19780.

[43] Son SM, Park SJ, Breusegem SY et al. p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson-Gilford progeria syndrome. Nat Cell Biol 2024;26:235–249.

[44] Stacpoole PW. Therapeutic targeting of the Pyruvate Dehydrogenase Complex/Pyruvate Dehydrogenase Kinase (PDC/PDK) axis in cancer. J Natl Cancer Inst 2017;109:djx071.

[45] Su H, Yang F, Wang QT et al. VPS34 acetylation controls its lipid kinase activity and the initiation of canonical and non-canonical autophagy. Mol Cell 2017;67:907–921.e7.

[46] Sun L, Zhang H, Gao P. Metabolic reprogramming and epigenetic modifications on the path to cancer. Protein Cell 2022;13:877–919.

[47] Sun X, He L, Liu H et al. The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity. Cell Metab 2023;35:1563–1579.e8 e1568.

[48] Thompson PR, Wang D, Wang L et al. Regulation of the p300 HAT domain via a novel activation loop. Nat Struct Mol Biol 2004;11:308–315.

[49] Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324:1029–1033.

[50] Varner EL, Trefely S, Bartee D et al. Quantification of lactoyl-CoA (lactyl-CoA) by liquid chromatography mass spectrometry in mammalian cells and tissues. Open Biol 2020;10:200187.

[51] Wang Q, Zhang Y, Yang C et al. Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. Science 2010;327:1004–1007.

[52] Wang DL, Kon N, Lasso G et al. Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. Nature 2016;538:118–122.

[53] Whitehouse S, Randle PJ. Activation of pyruvate dehydrogenase in perfused rat heart by dichloroacetate (Short Communication). Biochem J 1973;134:651–653.

[54] Xie M, Bu Y. SKA2/FAM33A: a novel gene implicated in cell cycle, tumorigenesis, and psychiatric disorders. Genes Dis 2019;6:25–30.

[55] Yokomizo C, Yamaguchi K, Itoh Y et al. High expression of p300 in HCC predicts shortened overall survival in association with enhanced epithelial mesenchymal transition of HCC cells. Cancer Lett 2011;310:140–147.

[56] Yu J, Chai P, Xie M et al. Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. Genome Biol 2021;22:85.

[57] Zhang D, Tang Z, Huang H et al. Metabolic regulation of gene expression by histone lactylation. Nature 2019;574:575–580.

[58] Zhang Y, Luo L, Xu X et al. Acetylation is required for full activation of the NLRP3 inflammasome. Nat Commun 2023;14:8396.

[59] Zhao S, Xu W, Jiang W et al. Regulation of cellular metabolism by protein lysine acetylation. Science 2010;327:1000–1004.

[60] Zhao D, Zou SW, Liu Y et al. Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell 2013;23:464–476.

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2024 The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.