Lactic acid is a by-product of aerobic glycolysis (the Warburg effect), and it has been reported to play a role in epigenetic modifications. One of the hallmarks of tumors is the Warburg effect, which produces large amounts of lactate through glycolysis using glucose and creates an acidic tumor microenvironment. Lactic acid, which acts as a precursor, causes the lactyl group to be added to the lysine side chain of the protein substrate, known as lysine lactation (Kla), especially on histones, which directly regulates gene transcription in chromatin. Physiologically, lactated histones are involved in immune cell homeostasis, stem cell differentiation, and early embryonic development. Pathologically, elevated histone lactation modifications have been associated with ulcerative colitis, pulmonary fibrosis, sepsis, systemic lupus erythematosus, and ocular tumors.
Most research on lactation is limited to the nucleus, particularly histones associated with transcriptional activation and repression of balanced genes, leading to the initiation and progression of disease. Although recent evidence suggests that lactation is present in a variety of cellular proteins, there is currently no clear evidence for the presence and function of lactation in the nucleus. Studies have analyzed the entire lactose metabolome in hepatocellular carcinoma, but little attention has been paid to the underlying mechanisms of lactose-mediated changes in cell function.
Functional studies of lactate-modified proteins or pathways require an understanding of their catalytic enzymes and substrates. Screening studies of lysine deacetylases in 18 mammals have shown that histone deacetylases have the ability to remove lactylated deacetylases from histones. However, these studies do not provide a comprehensive understanding of the regulatory mechanisms of lactoseization.
As a metabolite lactic acid, it not only acts as a substrate to provide energy to support cell growth and development, but also acts as an important signaling molecule to influence the biochemical functions of intracellular proteins and regulate the biological functions of different types of cells. At present, lactation, as a new epigenetic modification and oncogenic signaling, provides a promising and potential research direction, and the metabolism and functional mechanism of lactate is becoming one of the hot areas of tumor research.
Although it is generally believed that abnormalities in lactation modification are associated with various diseases caused by excessive glycolytic metabolism. However, the regulatory molecules and downstream protein targets of lactation remain largely unclear. The study by Xie et al. looked at overall lactation in colorectal cancer that was negatively associated with prognosis. Among the emulsified proteins detected in colorectal cancer, emulsification of eEF1A2K408 was found to lead to prolonged translation and enhanced protein synthesis, thereby promoting tumorigenesis. By screening for eEF1A2-interacting proteins, it was found that KAT8 is a lysine acetyltransferase that acts as a panlactic writer responsible for lactation on many protein substrates involved in different biological processes. In the hyperlactic tumor microenvironment, knockdown of KAT8 inhibited tumor growth in colorectal cancer. Therefore, the use of the KAT8-eEF1A2 lactation axis can meet the translation needs of increased carcinogenic adaptation. As a lactoacyltransferase, KAT8 may suggest a potential therapeutic target for colorectal cancer.
[References]
1. Xie B. et al., KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis. PNAS, 2024. Vol. 121
2. Zhang Y. et al., Lactate: The Mediator of Metabolism and Immunosuppression. Front. in Endo.2022, Vol 13