Mechanism and application of lactylation in cancers

Abstract

Lactate is a crucial product of cancer metabolism, creating an acidic environment that supports cancer growth and acts as a substrate for lactylation. Lactylation, a newly discovered epigenetic modification, plays a vital role in cancer cell signaling, metabolic reprogramming, immune response, and other functions. This review explores the regulation of lactylation, summarizes recent research on its role in cancers, and highlights its application in cancer drug resistance and immunotherapy. These insights aim to provide new avenues for targeting lactylation in cancer therapy.

Keywords: Cancer; Cancer resistance; Immunotherapy; Lactylation.

Fig. 1

Application of lactylation in cancer. A: Lactylation induces transcription of target genes. B: Lactylation regulates chromatin remodeling. C: Lactylation stimulates neoangiogenesis. D: Lactylation promotes repair genes transcription. E: Lactylation modulates macrophages. F: Lactylation controls muscle structure and function

Fig. 2

Regulation of lactylation. A: GLUT3 overexpression significantly decreased levels of LDHA, L-lactic acid, H3 K9, H3 K18, and H3 K56. When the glycolysis pathway is over-activated and too much lactic acid is produced, the activity of the upstream enzyme ALDOA will be inhibited by lactylation, inhibiting glycolysis. NUSAP1 up-regulated LDHA promoted lactylation and inhibited the protein degradation of NUSAP1. HIF-1α lactate modifies HIF-1α protein, while HIF-1α promotes glucose uptake and glycolysis. B: EP300 inhibited histone lactylation and down-regulated YTHDF2 expression. CBP inhibits lactylation at MRE11 K673. p300/CBP promotes the lactylation of HMGB1. Histone deacetylase SIRT2 inhibits the lactylation of METTL16. SIRT3 inhibits the lactylation of cyclin CCNE2. SIRT6 acts as a cancer suppressor by regulating lactate production

Fig. 3

Histone lactylation and cancer progression. A: Lactylation of H3 K18 promotes the expression of oncogene YTHDF2 in cancer cells. B: GPR37 enhances glycolysis and histone H3 K18 lactylation through the Hippo pathway, promoting liver metastasis of colorectal cancer. C: H3 K18 lactylation promotes c-Myc expression to promote the proliferation of breast cancer cells. D: DML can inhibit the lactylation of H3 K9 and K56 sites and thus inhibit liver cancer. RJA inhibits the development of HCC by interfering with lactylation and inhibiting lactylation at H3 K9 and H3 K14 sites. E: FGS inhibits non-small cell lung cancer by targeting H3 histone lactylation. F: Lactylation on H3 K14 and H3 K18 inhibited SLC25 A29 transcription and affected the proliferation, migration and apoptosis of lung adenocarcinoma endothelial cells. G: Histone H4 lactylation can promote the expression of glycolytic-related genes and promote the proliferation and migration of NSCLC. H: Lactylation of H4 K12 activates the expression of multiple genes necessary for the proliferation of undifferentiated thyroid carcinoma (ATC), and the blocking of cellular lactylation mechanisms in combination with BRAFV600E inhibitors can synergistically inhibit the malignant progression of thyroid cancer. I: The AKR1B10 promotes glycolysis and stimulates H4 K12 la to activate CCNB1 transcription. While silencing AKR1B10 increases the sensitivity of the drug PEM in vitro and in vivo. J: Histone lactylation promotes the progression of ccRCC by activating the transcription of platelet-derived growth factor receptor β (PDGFRβ), while PDGFRβ signal transduction stimulates histone lactylation. K: The combination of histone lactylation and PDGFRβ significantly enhanced the therapeutic effect. CircXRN2 affects the glycolysis process by regulating the Hippo signaling pathway, inhibits lactate production and affects the lactylation of histone H3 K18. L: Increased lactylation of histone H4 K8 upregulates transcription of LINC00152 and promotes invasion and migration of colorectal cancer. M: Lactylation of histone H3 can increase the expression of LINC01127, leading to the promotion of GBM cell self-renewal

Fig. 4

Non-histone lactylation and cancer progression. A: The lactylation of CENP at lysine 124 (K124) promotes the activation of CENPA and promotes the proliferation of HCC cells and cancer growth. B: GPC3 knockdown decreased c-myc lactylation, further reducing the protein stability of c-myc and cell viability and dryness of HCC cells. C: Lactylation of hypoxia-inducing factor HIF-1α in prostate cancer cells can stabilize the protein HIF-1α itself, thereby promoting the transcription of downstream genes. D: Lactylation of CALML5 is associated with cutaneous melanoma. E: The translation initiation factor BZW2 promotes the malignant progression of LUAD by promoting glycosylation-mediated lactate production and lactylation of IDH3G. F: Aldob-mediated lactic acid production enhances the stability of CEACAM6 protein by increasing CEACAM6 Kla and promotes the malignant progression of colorectal cancer. G: LDHA binds and promotes the lactylation of VEGFR2 and VE-cadherin, and increases their protein expression. These two molecules act as markers of angiogenesis simulation VM to promote the proliferation, migration, and invasion of GBM cells

Fig. 5

Lactylation and immunotherapy. A: Lactic acid promotes the expression of Mettl3 through Kla, thus promoting the malignant progression of colon cancer, and lactic acid can directly mediate the lactylation of Mettl3 to promote immunosuppression. B: Lactic acid promotes hepatocellular carcinoma by modulating MOESIN lactylation and enhancing TGF-β signaling. C: Evodiine can inhibit the expression of histone lactylation, HIF1 A and PD-L1, thereby inhibiting the proliferation of prostate cancer cells. D: Increased lactate promotes the lactylation of histone H3 K18 and upregulates the expression of CD39, CD73 and CCR8. Inhibition of lactate LDHA combined with CAR-T therapy has better efficacy against GBM