The relationship and clinical significance of lactylation modification in digestive system tumors

Abstract

Lactylation, an emerging post-translational modification, plays a pivotal role in the initiation and progression of digestive system tumors. This study presents a comprehensive review of lactylation in digestive system tumors, underscoring its critical involvement in tumor development and progression. By focusing on metabolic reprogramming, modulation of the tumor microenvironment, and the molecular mechanisms regulating tumor progression, the potential of targeting lactylation as a therapeutic strategy is highlighted. The research reveals that lactylation participates in gene expression regulation and cell signaling by affecting the post-translational states of histones and non-histone proteins, thereby influencing metabolic pathways and immune evasion mechanisms in tumor cells. Furthermore, this study assesses the feasibility of lactylation as a therapeutic target, providing insights for clinical treatment of gastrointestinal cancers. Future research should concentrate on elucidating the mechanisms of lactylation, developing efficient lactylation inhibitors, and validating their therapeutic efficacy in clinical trials, which could transform current cancer treatment and immunotherapy approaches. In summary, this review emphasizes the crucial role of lactylation in tumorigenesis and progression through a detailed analysis of its molecular mechanisms and clinical significance.

Keywords: Digestive system tumors; Epigenetics; Lactate; Lactylation; Tumor microenvironment.

Fig. 1

Production of lactate and lactylation. When cellular oxygen demand does not exceed the supply, glucose undergoes glycolysis, producing pyruvate, which enters the mitochondria and is oxidized to CO2 and H2O through the TCA cycle. However, under anaerobic or low-oxygen conditions inhibiting the TCA cycle, in order to sustain glycolysis, pyruvate is reduced to lactate in the cytoplasm by LDH. Specifically, glucose in the cytoplasm undergoes a series of classical catalytic reactions to convert into pyruvate. Pyruvate, instead of entering the mitochondria for oxidation, is directly reduced to lactate by LDH. Additionally, glutamine entering the cytoplasm is converted to glutamate through glutaminase. Then, glutamate is transformed into α-ketoglutaric acid through glutamate dehydrogenase and enters the TCA cycle. In this cycle, carbon derived from glutamine is converted to oxaloacetate, then transformed into malate and exits the mitochondria. Subsequently, through cytoplasmic malate dehydrogenase, it is converted to NADPH and pyruvate, further reduced to lactate by LDH. Lactate metabolism in cells involves two pathways. Firstly, lactate is oxidized to pyruvate, which enters the TCA cycle after conversion by pyruvate dehydrogenase. On the other hand, lactate can be converted to lactyl-CoA, which is catalyzed by histone acetyltransferase and participates in histone Kla. Simultaneously, lactyl-CoA is also involved in non-histone Kla. LDH: lactate dehydrogenase. PDH: pyruvate dehydrogenase. PEPCK: phosphoenolpyruvate carboxykinase. GLS: glutaminase. GLUD: glutamate dehydrogenase. TAs: aspartate or alanine transaminase. α-KG: α-ketoglutaric acid. HATs: histone acetyltransferases. The figure was created using Biorender.com

Fig. 2

Lactate metabolism, lactylation and digestive system tumors. In tumors of the digestive system, lactate-mediated lactylation through the glycolytic pathway is regulated by various mechanisms. This regulation promotes tumor initiation, proliferation, migration, and invasion. Some substances, such as Rh4, inhibit glycolysis by reducing lactate production and glucose uptake, which demonstrates anti-tumor effects. Other substances like Penfluridol, DML, 2-DG, miR-30d-5p, miR-181b-5p, and miR-139-5p suppress tumor progression by inhibiting the glycolytic pathway. Additionally, glycolysis and lactate-mediated histone lactylation (such as H3K18la, H3K56la, H3K9la, H3K14la) play a role in tumor initiation. Histone lactylation modification also increases the expression of METTL3, which, through mediating RNA m6A modification, enhances the translation efficiency of JAK1, thereby activating the JAK1/STAT3 pathway. This transformation induces M2 polarization of tumor-associated macrophages, which suppresses the anti-tumor immune response. The PCSK9-activated PI3K/AKT pathway exhibits similar effects. Histone lactylation also promotes RUBCNL-mediated autophagy, which enhances tumor cell resistance. Both histone and non-histone lactylation levels are induced by LPS and hypoxia treatment, promoting tumor cell migration and invasion. Royal jelly acid specifically inhibits lactylation at H3K9 and H3K14 sites, demonstrating its role in inhibiting tumor proliferation, migration, and apoptosis. Lactate can also modify the Moesin protein, enhancing its interaction with the TGF-β signaling pathway. NUSAP1, a microtubule-associated protein, binds to c-Myc and HIF-1α, acting on the LDHA gene promoter region to upregulate LDHA expression. LDHA, as a rate-limiting enzyme, promotes glycolysis and lactate production. Lactate, in turn, stabilizes NUSAP1 protein through the induction of lactylation, reducing its degradation. m6A: N6-methyladenosine. PDHX: Pyruvate dehydrogenase complex component X. PKM2: Pyruvate kinase M2. PFKL: Phosphofructokinase, liver type. 2-DG: 2-deoxy-d-glucose. LDHA: Lactate dehydrogenase A. Rh4: a Ginsenoside. The figure was created using Biorender.com

Fig. 3

Lactate-mediated immunosuppression in the tumor microenvironment. The tumor microenvironment consists of tumor cells, tumor-associated immune cells, and tumor-associated fibroblasts, among others. In this microenvironment, lactate plays an immunosuppressive role by inducing, recruiting, and regulating immunosuppressive cells to promote tumor development. Lactate modifies histones directly, inhibiting signaling pathways. The most hypoxic regions in the tumor microenvironment typically exhibit the highest lactate concentrations, with cells relying predominantly on glycolysis as their main metabolic pathway. Lactate lowers the intracellular pH of immune cells and inhibits various immune cell activities. It suppresses the differentiation, activation, migration, and cytokine production of DCs, leading to a simultaneous inhibition of cytotoxic T cells, reducing their activation levels and cytokine production. Lactate inhibits the activity of NK cells and promotes apoptosis. It suppresses M1 polarization in macrophages while promoting their conversion to the M2 phenotype. Conversely, lactate promotes the maintenance of immunosuppressive function in MDSCs in an acidic environment, contributing to tumor occurrence and progression by regulating MSDCs. DCs: Dendritic cells. NK cells: Natural killer cells. MSDCs: Myeloid-derived suppressor cells. The figure was created using Biorender.com