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Beyond metabolic waste: lysine lactylation and its potential roles in cancer progression and cell fate determination

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Abstract

Background

Lactate is an important metabolite derived from glycolysis under physiological and pathological conditions. The Warburg effect reveals the vital role of lactate in cancer progression. Numerous studies have reported crucial roles for lactate in cancer progression and cell fate determination. Lactylation, a novel posttranslational modification (PTM), has provided a new opportunity to investigate metabolic epigenetic regulation, and studies of this process have been initiated in a wide range of cancer cells, cancer-associated immune cells, and embryonic stem cells.

Conclusion

Lactylation is a novel and interesting mechanism of lactate metabolism linked to metabolic rewiring and epigenetic remodeling. It is a potential and hopeful target for cancer therapy. Here, we summarize the discovery of lactylation, the mechanisms of site modification, and progress in research on nonhistone lactylation. We focus on the potential roles of lactylation in cancer progression and cell fate determination and the possible therapeutic strategies for targeting lysine lactylation. Finally, we suggest some future research topics on lactylation to inspire some interesting ideas.

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Data Availability

All data associated with this study are presented in the paper. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

PTM:

posttranslational modification

MS:

mass spectrometry

Kla:

lysine lactylation

BMDM:

mouse bone marrow-derived macrophage

lactyl-CoA:

lactyl-coenzyme A

HDAC:

histone deacetylase

LGSH:

lactyl-glutathione

MGO:

methylglyoxal

GLO:

glyoxalase

GSH:

glutathione

GLO 1&2:

glyoxalase I and II

AI:

artificial intelligence

HMGB1:

high mobility group box-1

TME:

tumor microenvironment

OXPHOS:

oxidative phosphorylation

MCT:

monocarboxylate transporter

TAM:

tumor-associated macrophage

Treg:

regulatory T cell

Kxla:

lactylation at the Lys x site (x is a number)

PD-1:

programmed cell death protein 1

YTHDF2:

YTH N6-methyladenosine RNA-binding protein 2

GPR81:

G-protein-coupled receptor 81

HyKxla:

lactylation at the Lys x site of histone y (x and y are numbers)

iPSCs:

pluripotent stem cells

HFSCs:

hair follicle stem cells

PSC:

pluripotent stem cell

Glis1:

Gli-like transcription factor 1

LDH:

lactate dehydrogenase

LDHA:

lactate dehydrogenase A

CREB:

cAMP response element-binding protein

KAT:

lysine acetyltransferase

CBP:

CREB-binding protein

Kac:

lysine acetylation

NF-κB:

nuclear factor κB

KDAC:

lysine deacetylase

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Acknowledgements

We thank Professor Yu Shi, Professor You-Hong Cui, and Professor Liang Yi for their constructive suggestions. We also thank Si-yi Zhang for providing language assistance.

Funding

This study was supported by grants from the National Key Research and Development Program of China (2022YFA1104704 to SCY), Major Projects of the National Natural Science Foundation of China (U22A20325 to SCY), General Projects of the National Natural Science Foundation of China (82273419 to JW), and Major Projects of Technological Innovation and Application Development Foundation in Chongqing (CSTB2022TIAD-STX0012 to SCY).

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    1. Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China

      Jun-han Wang, Ling Mao, Jun Wang, Xiao Zhang, Min Wu, Qian Wen & Shi-cang Yu

    2. International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China

      Jun-han Wang, Ling Mao, Jun Wang, Xiao Zhang, Min Wu, Qian Wen & Shi-cang Yu

    3. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China

      Jun-han Wang, Ling Mao, Jun Wang, Xiao Zhang, Min Wu, Qian Wen & Shi-cang Yu

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    All authors contributed to the study conception and design. Jun-han Wang, Ling Mao and Shi-cang Yu contributed significantly to the analyses and manuscript preparation. The first draft of the manuscript was written by Jun-han Wang and Ling Mao. Jun Wang, Ling Mao, Xiao Zhang, Min Wu and Qian Wen participated in the analysis through constructive discussions. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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    Wang, Jh., Mao, L., Wang, J. et al. Beyond metabolic waste: lysine lactylation and its potential roles in cancer progression and cell fate determination. Cell Oncol. 46, 465–480 (2023). https://doi.org/10.1007/s13402-023-00775-z

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