Functions and mechanisms of lactylation in carcinogenesis and immunosuppression

Abstract

As critical executors regulating many cellular operations, proteins determine whether living activities can be performed in an orderly and efficient manner. Precursor proteins are inert and must be modified posttranslationally to enable a wide range of protein types and functions. Protein posttranslational modifications (PTMs) are well recognized as being directly associated with carcinogenesis and immune modulation and have emerged as important targets for cancer detection and treatment. Lactylation (Kla), a novel PTM associated with cellular metabolism found in a wide range of cells, interacts with both histone and nonhistone proteins. Unlike other epigenetic changes, Kla has been linked to poor tumor prognosis in all current studies. Histone Kla can affect gene expression in tumors and immunological cells, thereby promoting malignancy and immunosuppression. Nonhistone proteins can also regulate tumor progression and treatment resistance through Kla. In this review, we aimed to summarize the role of Kla in the onset and progression of cancers, metabolic reprogramming, immunosuppression, and intestinal flora regulation to identify new molecular targets for cancer therapy and provide a new direction for combined targeted therapy and immunotherapy.

Keywords: Warburg effect; immunosuppression; lactylation (Kla); metabolic reprogramming; tumor microenvironment (TME).

Figure 1

The metabolic process of lactate. Lactate can be created intracellularly by glycolysis catalyzed by LDH, or it can be taken up from the outside via MCT1. Intracellular lactate inhibits glycolytic enzymes while promoting the tricarboxylic acid cycle, generating a negative feedback loop. Lactate can also be converted to lactoyl-CoA, which is involved in the lactylation of histone and non-histone proteins. HK-1, hemokinin-1; G6PD, glucose 6-phosphate dehydrogenase; PKM, glycolytic enzyme pyruvate kinase M; MCT1, monocarboxylate transporters 1; LDH, lactate dehydrogenase; PDH, Pyruvate dehydrogenase; SDH, succinate dehydrogenase; IDH, isocitrate dehydrogenase; TCA, Tricarboxylic acid; HDAC, histone deacetylase; Kla, lactylation.

Figure 2

The regulatory process of lactylation. There are two known modification pathways for lactylation. L-lactate can form lactoyl-CoA, which mediates lactylation under the catalysis of P300. In addition, methylglyoxal can form LGSH under the catalysis of GLO1, and LGSH can also mediate the lactylation of proteins, which does not require enzyme catalysis. LGSH can be decomposed into glutathione and D-lactate under the action of GLO2. Both L-and D-lactate-mediated lactylation were abolished by HDAC3. LGSH, Lactoylglutathione; GLO, glyxoalase.

Figure 3

Lactylation regulates the function of immune cells to mediate immunosuppression. In TAM, histone lactylation will lead to the up-regulation of M2 phenotypically related genes, thereby mediating the M2 polarization. In TIMs, histone lactylation promote the expression of METTL3, and METTL3 mediates the m6A modification of JAK1 mRNA. At the same time, there are also lactylation sites in METTL3 that allow it to bind to the target RNA. Moesin can reduce the expression of TGF-β receptor and inhibit the production of Treg cells to restore anti-tumor immunity. Lactate can inhibit the function of moesin by promoting Lys72 site lactylation to mediate the generation of Treg cells and promote the immune escape of tumor cells. In conclusion, lactylation is closely related to the immunosuppression of tumors. LPS, Lipopolysaccharide; IFN γ, Interferon-gamma; IL-4, interleukin-4; IL-13, interleukin-13; TAM, tumor-associated macrophages; TIM, tumor -infiltrating myeloid cells; Arg1, arginase 1; METTL3, methyltransferase-like 3; JAK1, Janus Kinase 1; M6A, N6-methyladenosine; TGF-β, transforming growth factor beta.

Figure 4

The mechanism of intestinal flora regulating the occurrence and development of tumors. Intestinal bacteria can directly cause intracellular DNA damage by producing genotoxins, or activate the NF-κB and STAT3 pathway by promoting cytokines secretion to promote tumorigenesis. Intestinal bacteria can also activate a range of oncogenic pathways. Increased release and translocation of β-catenin into the nucleus through degradation of the E-cadherin/β-catenin complex leads to aberrant activation of WNT signaling associated with various cancers. Besides, they can lead to the invasion and metastasis of cancer by activating TLR4/Keap1/NRF2 signaling. Furthermore, LPS produced by bacteria has been shown to promote the Kla of histones, which in turn promotes tumor progression. LPS, Lipopolysaccharide; TLR4, Toll-like receptor 4; Nrf2, Nuclear factor E2-related factor 2; NF-κB, Noncanonical nuclear factor-kappaB; STAT3, ignal transducer and activator of transcription 3.