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

doi:10.1093/procel/pwae052

journal article Open Access Sep 23, 2024

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

Protein & Cell Vol. 16 No. 1 pp. 49-63 · Oxford University Press (OUP)

View at Publisher Save 10.1093/procel/pwae052

Abstract

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.

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References

60

[1]

An "PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation" Cell Death Dis (2023) 10.1038/s41419-023-05952-4

[2]

Bian "Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carb oxykinase sumoylation" Nat Commun (2017) 10.1038/ncomms14420

[3]

Cai "Phosphorylation of PDHA by AMPK drives TCA cycle to promote cancer metastasis" Mol Cell (2020) 10.1016/j.molcel.2020.09.018

[4]

Lactate modulation of immune responses in inflammatory versus tumour microenvironments

Michelangelo Certo, Chin-Hsien Tsai, Valentina Pucino et al.

Nature Reviews Immunology 2021 10.1038/s41577-020-0406-2

[5]

Metabolic regulation of homologous recombination repair by MRE11 lactylation

Yuping Chen, Jinhuan Wu, Linhui Zhai et al.

Cell 2024 10.1016/j.cell.2023.11.022

[6]

DeBerardinis "We need to talk about the Warburg effect" Nat Metab (2020) 10.1038/s42255-020-0172-2

[7]

Depianto "Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin" Nat Genet (2010) 10.1038/ng.665

[8]

Eastlack "Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer" Mol Cancer (2018) 10.1186/s12943-018-0851-8

[9]

Fan "Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex" Mol Cell (2014) 10.1016/j.molcel.2013.12.026

[10]

Metabolic reprogramming and cancer progression

Brandon Faubert, Ashley Solmonson, Ralph J. DeBerardinis

Science 2020 10.1126/science.aaw5473

[11]

Feng "Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma" J Exp Clin Cancer Res (2020) 10.1186/s13046-020-01629-4

[12]

Gao "Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy" Nat Cell Biol (2020) 10.1038/s41556-020-0562-4

[13]

Guertin "Acetyl-CoA metabolism in cancer" Nat Rev Cancer (2023) 10.1038/s41568-022-00543-5

[14]

Han "IL-1beta-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance" Mol Cell (2023) 10.1016/j.molcel.2023.05.011

[15]

Haugrud "Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells" Breast Cancer Res Treat (2014) 10.1007/s10549-014-3128-y

[16]

Hiromasa "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) 10.1074/jbc.m308172200

[17]

Hou "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) 10.1007/s10120-022-01362-1

[18]

Huang "Acetylation-dependent SAGA complex dimerization promotes nucleosome acetylation and gene transcription" Nat Struct Mol Biol (2022) 10.1038/s41594-022-00736-4

[19]

Hui "Glucose feeds the TCA cycle via circulating lactate" Nature (2017) 10.1038/nature24057

[20]

HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia

Jung-whan Kim, Irina Tchernyshyov, Gregg L. Semenza et al.

Cell Metabolism 2006 10.1016/j.cmet.2006.02.002

[21]

Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments

Shogo Kumagai, Shohei Koyama, Kota Itahashi et al.

Cancer Cell 2022 10.1016/j.ccell.2022.01.001

[22]

Lei "Acetylation promotes BCAT2 degradation to suppress BCAA catabolism and pancreatic cancer growth" Signal Transduct Target Ther (2020) 10.1038/s41392-020-0168-0

[23]

Li "High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma" J Transl Med (2011) 10.1186/1479-5876-9-5

[24]

Li "Myc-mediated SDHA acetylation triggers epigenetic regulation of gene expression and tumorigenesis" Nat Metab (2020) 10.1038/s42255-020-0179-8

[25]

Li "METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions" Nat Commun (2022) 10.1038/s41467-022-34209-5

[26]

The Warburg Effect: How Does it Benefit Cancer Cells?

Maria V. Liberti, Jason W. Locasale

Trends in Biochemical Sciences 2016 10.1016/j.tibs.2015.12.001

[27]

Liu "The structural basis of protein acetylation by the p300/CBP transcriptional coactivator" Nature (2008) 10.1038/nature06546

[28]

Acetylation Targets the M2 Isoform of Pyruvate Kinase for Degradation through Chaperone-Mediated Autophagy and Promotes Tumor Growth

Lei Lv, Dong Li, Di Zhao et al.

Molecular Cell 2011 10.1016/j.molcel.2011.04.025

[29]

Ma "Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1" Nat Commun (2014) 10.1038/ncomms6212

[30]

Mullen "Genetically-defined metabolic reprogramming in cancer" Trends Endocrinol Metab (2012) 10.1016/j.tem.2012.06.009

[31]

Functions and mechanisms of non-histone protein acetylation

Takeo Narita, Brian T. Weinert, Chunaram Choudhary

Nature Reviews Molecular Cell Biology 2019 10.1038/s41580-018-0081-3

[32]

Nie "O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth" Nat Commun (2020) 10.1038/s41467-019-13601-8

[33]

Papandreou "HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption" Cell Metab (2006) 10.1016/j.cmet.2006.01.012

[34]

Park "Role of the pyruvate dehydrogenase complex in metabolic remodeling: differential pyruvate dehydrogenase complex functions in metabolism" Diabetes Metab J (2018) 10.4093/dmj.2018.0101

[35]

Patel "Regulation of mammalian pyruvate dehydrogenase complex by phosphorylation: complexity of multiple phosphorylation sites and kinases" Exp Mol Med (2001) 10.1038/emm.2001.32

[36]

Patel "The pyruvate dehydrogenase complexes: structure-based function and regulation" J Biol Chem (2014) 10.1074/jbc.r114.563148

[37]

The hallmarks of cancer metabolism: Still emerging

Natalya N. Pavlova, Jiajun Zhu, Craig B. Thompson

Cell Metabolism 2022 10.1016/j.cmet.2022.01.007

[38]

Prajapati "Structural and functional analyses of the human PDH complex suggest a “Division-of-Labor” mechanism by local E1 and E3 clusters" Structure (2019) 10.1016/j.str.2019.04.009

[39]

Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis

Hyunsoo Rho, Alexander R. Terry, Constantinos Chronis et al.

Cell Metabolism 2023 10.1016/j.cmet.2023.06.013

[40]

Shen "Dual-targeting of aberrant glucose metabolism in glioblastoma" J Exp Clin Cancer Res (2015) 10.1186/s13046-015-0130-0

[41]

Shvedunova "Modulation of cellular processes by histone and non-histone protein acetylation" Nat Rev Mol Cell Biol (2022) 10.1038/s41580-021-00441-y

[42]

Smolle "A new level of architectural complexity in the human pyruvate dehydrogenase complex" J Biol Chem (2006) 10.1074/jbc.m601140200

[43]

Son "p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson-Gilford progeria syndrome" Nat Cell Biol (2024) 10.1038/s41556-023-01338-y

[44]

Stacpoole "Therapeutic targeting of the Pyruvate Dehydrogenase Complex/Pyruvate Dehydrogenase Kinase (PDC/PDK) axis in cancer" J Natl Cancer Inst (2017) 10.1093/jnci/djx071

[45]

Su "VPS34 acetylation controls its lipid kinase activity and the initiation of canonical and non-canonical autophagy" Mol Cell (2017) 10.1016/j.molcel.2017.07.024

[46]

Sun "Metabolic reprogramming and epigenetic modifications on the path to cancer" Protein Cell (2022) 10.1007/s13238-021-00846-7

[47]

The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity

Xuedan Sun, Lifang He, Hong Liu et al.

Cell Metabolism 2023 10.1016/j.cmet.2023.07.005

[48]

Thompson "Regulation of the p300 HAT domain via a novel activation loop" Nat Struct Mol Biol (2004) 10.1038/nsmb740

[49]

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

Matthew G. Vander Heiden, Lewis C. Cantley, Craig B. Thompson

Science 2009 10.1126/science.1160809

[50]

Varner "Quantification of lactoyl-CoA (lactyl-CoA) by liquid chromatography mass spectrometry in mammalian cells and tissues" Open Biol (2020) 10.1098/rsob.200187

Showing 50 of 60 references

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Details

Published: Sep 23, 2024
Vol/Issue: 16(1)
Pages: 49-63
License: View

Authors

Z

Zetan Jiang

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 ,; 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 ,

N

Nanchi Xiong

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 ,; 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 ,; Insitute of Health and Medicine, Hefei Comprehensive National Science Center , Hefei 230601,

R

Ronghui Yan

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 ,; 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 ,

S

Shi-ting Li

Medical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University , Guangzhou 510080 ,

H

Haiying Liu

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 ,; 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 ,

Q

Qiankun Mao

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 ,

Y

Yuchen Sun

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 ,

S

Shengqi Shen

Medical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University , Guangzhou 510080,

L

Ling Ye

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 ,

P

Ping Gao

Medical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University , Guangzhou 510080,

P

Pinggen Zhang

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 ,; 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 ,

W

Weidong Jia

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 ,

H

Huafeng Zhang

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 ,; 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 ,; Insitute of Health and Medicine, Hefei Comprehensive National Science Center , Hefei 230601,

Funding

National Natural Science Foundation of China Award: 81930083

National Key R&D Program of China Award: 2022YFA1304504

Chinese Academy of Sciences Award: XDB39000000

Global Select Project Award: DJK-LX-2022001

Institute of Health and Medicine, Hefei Comprehensive National Science Center and the Fundamental Research Funds for the Central Universities Award: WK9100000051

Cite This Article

Zetan Jiang, Nanchi Xiong, Ronghui Yan, et al. (2024). PDHX acetylation facilitates tumor progression by disrupting PDC assembly and activating lactylation-mediated gene expression. Protein & Cell, 16(1), 49-63. https://doi.org/10.1093/procel/pwae052

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

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