Lactylation in tumor: mechanisms and therapeutic potentials

Abstract

Lactate, a central product of glucose metabolism, plays a vital role in energy supply and signal transduction, and it also participates in gene transcription regulation through lactylation. Metabolic reprogramming is a key feature of tumor cells and highlights the important role of lactylation in cancer development. Recent studies have emphasized the significant regulatory roles of lactylation in cancer, suggesting that it may serve as a potential target for treatment. This review discusses the mechanisms, regulation, and functions of lactylation in cancer. It also explores the possible significance of lactylation as a marker for the diagnosis and therapy of tumor, and evaluates the therapeutic prospects of targeting lactylation. While the precise mechanisms of lactylation in cancer regulation require further investigation, its significant influence indicates promising avenues for future research.

Keywords: lactate; lactylation; post-translational modifications; tumor metabolism; tumor microenvironment.

Figure 1

The mechanisms of lactylation modification. Lactylation modification occurs through enzymatic reactions using lactyl-CoA as the substrate and non-enzymatic reactions using LGSH as the substrate. The enzymatic lactylation process is mediated by enzymes such as P300, AARS1, and AARS2, and can take place in the nucleus, cytoplasm, and mitochondrial matrix. Non-enzymatic reactions can occur in the cytoplasm.HK, Hexokinase; GPI, Glucose-6-phosphate isomerase; PFK-1, Phosphofructokinase-1; TPI, Triose phosphate isomerase; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; PGK, Phosphoglycerate kinase; PGM, Phosphoglycerate mutase; PK, Pyruvate kinase; LDH, Lactate dehydrogenase; ACSS2, Acetyl-CoA synthetase 2; AARS1, Aminoacyl-tRNA synthetase 1; GLO1, Glyoxalase 1; ATP, Adenosine triphosphate; GSH, Glutathione; MGO, Methylglyoxal; P300, E1A binding protein p300; CBP, CREB-binding protein; KAT8, lysine acetyltransferase 8. Figure created in https://BioRender.com.

Figure 2

Lactylation in digestive system tumors. In digestive system tumors, lactate can participate in tumor progression through lactylation modification. Lactylation at histone sites such as H3K18, H4K12, H3K9, and H3K56 can promote tumor progression by regulating gene expression. Lactylation of non-histone proteins also participates in tumor progression by altering protein structure and interactions with other proteins. NUSAP1, Nucleolar and spindle associated protein 1; CCNE2, Cyclin E2; AK2, Adenylate Kinase 2; eEF1A2, Eukaryotic translation elongation factor 1 alpha 2; MRE11, Meiotic recombination 11 homolog A; YAP, Yes-associated protein; TEAD1, TEA domain transcription factor 1; LDHA, Lactate dehydrogenase A; ALDOA, Aldolase A; DDX17, DEAD-box helicase 17; Ptdins3K, Phosphatidylinositol-3-Kinase; RUBCNL, Rubicon like autophagy enhancer; BECN1, Beclin 1; TTK, TTK protein kinase; BUB1B, BUB1 mitotic checkpoint serine/threonine kinase B; VCAM1, Vascular cell adhesion molecule 1; CXCL1, Chemokine (C-X-C Motif) Ligand 1; SOX2, SRY-Box Transcription Factor 2; PDAC, Pancreatic ductal adenocarcinoma; HCC, Hepatocellular carcinoma; GC, Gastric cancer; CRC, Colorectal cancer. Figure created in https://BioRender.com.

Figure 3

Lactylation in urogenital system tumor. In the urogenital system, histone lactylation can promote tumor progression by inducing gene transcription and activating downstream signaling. SPOP, Speckle-type POZ; LCN1, Lipocalin 1; VHL, Von hippel-lindau; PDGFRβ, Platelet-derived growth factor receptor β; USP39, Ubiquitin specific peptidase 39; PGK1, Phosphoglycerate kinase 1; SIRT1, Sirtuin 1; CNPY3, Canopy FGF signaling regulator 3. Figure created in https://BioRender.com.

Figure 4

Lactylation in Lung cancer. In lung cancer, lactate can participate in the energy metabolism, chemoresistance, and immune evasion of lung cancer through histone and non-histone lactylation modifications, ultimately leading to tumor progression. Treg, Regulatory T cells; AKR1B10, Aldo-keto reductase family 1 B10; BZW2, Basic leucine zipper and W2 domains 2; LDH, Lactate dehydrogenase; SOX9, Sex determining region Y box protein 9; IDH3G, Isocitrate dehydrogenase three non – catalytic subunit gamma; APOC2, Apolipoprotein C2; IGF1R, Insulin-like growth factor 1 receptor; MYC, MYC proto-oncogene; HK1, Hexokinase 1; CCNB1, Cyclin B1; SP1, Specificity protein 1; TERT, Telomerase reverse transcriptase; POM121, Pore membrane protein 121; AIM2, Absent in melanoma 2. Figure created in https://BioRender.com.