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Review
. 2023 Oct 27:14:1284344.
doi: 10.3389/fimmu.2023.1284344. eCollection 2023.

Histone lactylation regulates cancer progression by reshaping the tumor microenvironment

Junxing Qu  1 , Peizhi Li  2 , Zhiheng Sun  3
Affiliations
Review

Histone lactylation regulates cancer progression by reshaping the tumor microenvironment

Junxing Qu et al. Front Immunol. .

Abstract

As a major product of glycolysis and a vital signaling molecule, many studies have reported the key role of lactate in tumor progression and cell fate determination. Lactylation is a newly discovered post-translational modification induced by lactate. On the one hand, lactylation introduced a new era of lactate metabolism in the tumor microenvironment (TME), and on the other hand, it provided a key breakthrough point for elucidation of the interaction between tumor metabolic reprogramming and epigenetic modification. Studies have shown that the lactylation of tumor cells, tumor stem cells and tumor-infiltrating immune cells in TME can participate in the development of cancer through downstream transcriptional regulation, and is a potential and promising tumor treatment target. This review summarized the discovery and effects of lactylation, as well as recent research on histone lactylation regulating cancer progression through reshaping TME. We also focused on new strategies to enhance anti-tumor effects via targeting lactylation. Finally, we discussed the limitations of existing studies and proposed new perspectives for future research in order to further explore lactylation targets. It may provide a new way and direction to improve tumor prognosis.

Keywords: cancer therapy; epigenetic modification; immune cells; lactylation; tumor microenvironment.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Lactate acts as a signaling molecule to affect gene transcription and immune evasion via histones and non-histone lysine lactylation and participate in cancer progression. Lactylation on HIF1α promotes KIAA1199 expression and prostate cancer progression. Lactylation upregulates MYCN and ASCL2 expression and thus promotes drug resistance. Increased H4K12 lactylation level causes cell cycle deregulation and ATC progression. Lactate promotes the upregulation of METTL3 in TIMs via inducing lactylation of H3K18 and colon cancer progression. Lactylation of lysine at position K28 of AK2 protein promotes HCC deterioration. H3K18 lactylation promotes YTHDF2 expression and thus promoting P53 and PER1 degradation. Histone lactylation in macrophages promotes a shift to the immunosuppressive M2 macrophage phenotype. Lactylation of K183 directly occur in transcription factor YY1, which promotes FGF2 expression and proliferative retinopathy progression. Lactylation promotes IDH3G expression and NSCLC. Histone lactylation on LINC0052 promoter promotes CRC progression. H3K18 lactylation promotes PDGFRβ expression and ccRCC progression. Lactylation of lysine at position K72 of MOESIN protein improves the interaction of MOESIN with TGF-β receptor I and regulates effector Tregs generation. Abbreviation: Kla, histone lysine lactylation; GLUT1, glucose transporter type 1; MCT1/4, monocarboxylate transporter 1/4; ATC, Anaplastic thyroid cancer; METTL3, m6A methyltransferase-like 3; AK2, adenylate kinase 2; YTHDF2, YTH Domain Family Protein 2; ccRCC, clear cell renal cell carcinoma; NSCLC, non-small cell lung cancer.
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References

    1. Li X, Yang Y, Zhang B, Lin X, Fu X, An Y, et al. . Lactate metabolism in human health and disease. Signal Transduct Target Ther (2022) 7(1):305. doi: 10.1038/s41392-022-01151-3 - DOI - PMC - PubMed
    1. Liu X, Zhang Y, Li W, Zhou X. Lactylation, an emerging hallmark of metabolic reprogramming: current progress and open challenges. Front Cell Dev Biol (2022) 10:972020. doi: 10.3389/fcell.2022.972020 - DOI - PMC - PubMed
    1. Lin J, Liu G, Chen L, Kwok HF, Lin Y. Targeting lactate-related cell cycle activities for cancer therapy. Semin Cancer Biol (2022) 86(Pt 3):1231–43. doi: 10.1016/j.semcancer.2022.10.009 - DOI - PubMed
    1. Moreno-Yruela C, Zhang D, Wei W, Baek M, Liu W, Gao J, et al. . Class I histone deacetylases (Hdac1-3) are histone lysine delactylases. Sci Adv (2022) 8(3):eabi6696. doi: 10.1126/sciadv.abi6696 - DOI - PMC - PubMed
    1. Yang K, Xu J, Fan M, Tu F, Wang X, Ha T, et al. . Lactate suppresses macrophage pro-inflammatory response to lps stimulation by inhibition of Yap and Nf-Kappab activation via Gpr81-mediated signaling. Front Immunol (2020) 11:587913. doi: 10.3389/fimmu.2020.587913 - DOI - PMC - PubMed

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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work is supported by grants from National Natural Science Foundation youth fund of China (32200714); Henan Normal University Research Launch Foundation (20220099) to ZS; Xinxiang Medical University Research Launch Foundation (505501) to JQ.