A growing body of research suggests that lactic acid is a useful metabolic fuel, a precursor to gluconeogenesis, and a signaling molecule for tumor survival and development. In addition, lactate also regulates the tumor microenvironment and epigenetic modification of genes through histone lactylation. The role of lactation and the precise molecular mechanisms underlying lactation modification have not yet been fully elucidated. Therefore, it is of great significance to comprehensively elucidate the effects of lactate on epigenetic modification and gene expression during tumor progression. Assessing the lactation level of histones in tumor tissues and elucidating their mechanisms in the regulation of gene expression has the potential to provide a new avenue for cancer therapy.
For normal cells, cellular respiration metabolism is the main and preferred source of energy, but cancer cells have their own understanding of energy acquisition, even in the presence of sufficient oxygen, they prefer glycolysis rather than respiration to obtain energy, which also represents the abnormal metabolic process of cancer preference for aerobic glycolysis, which is also known as the "Warburg effect".
It is precisely because of this special metabolic mechanism that cancer cells consume glucose at a high rate, so a large amount of lactic acid, a metabolite is produced. For example, after we exercise, muscle soreness is related to the accumulation of lactic acid, which will gradually clear over time, and the soreness will basically disappear after a few days. But cancer cells value lactic acid as a treasure, and they tend to prefer the acidic environment created by lactic acid.
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Previous studies have found that lactic acid can induce lactation of DNA damage repair proteins, leading to the occurrence of chemotherapy resistance, and lactic acid can also cause cachexia in cancer patients, resulting in extreme emaciation, exhaustion and other serious diseases.
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Recently, Professor Zhou Fangfang's team from Soochow University has once again added new evidence to the promotion of lactic acid for cancer, and the research team's paper published in Cell revealed that lactic acid can promote the lactation of p53 protein, resulting in abnormal activity of p53 protein, hindering the regulatory process of the cell cycle and promoting tumor development.
p53 is a classic tumor suppressor protein, and p53 mutations can be detected in many cancer types, or significant downregulation of p53 activity, and the regulatory mechanism of lactate belongs to the latter. When the researchers analyzed the TCGA breast cancer dataset, they found that some patients had normal p53 protein, but if their genetic characteristics corresponded to high lactate levels, the p53 signaling pathway of patients would be maintained at relatively low levels, which also indicates that the more lactate, the more severely impaired p53 function is. In the mouse experiment, the authors tried to inject the mice with sodium lactate, and the results showed that the p53 activity of the mice was also significantly inhibited.
In fact, the authors observed that the inhibition of p53 activity often occurs with p53 lactation, suggesting that excessive lactic acid accumulation in cancer cells will gradually shut down the original tumor suppressor protein activity, contributing to a more frantic growth process.
▲Schematic diagram of the study (Image source: Reference [1])
To explore which factors contribute to the lactation of p53, the authors performed a comprehensive genetic analysis of tumor cells. Using CRISPR screening, the authors found that the gene encoding alanyl-tRNA synthetase 1 (AARS1) is essential for the lactation of p53, and when they knocked out this gene, it re-increased the reactivity of p53 and removed the original inhibition. Tumor cells that have lost AARS1 have lost their former prestige even with the supply of sodium lactate, their growth rate is slowed, their clonogenic ability is reduced, and tumor grafts are difficult to develop.
The research team found that AARS1 acts like a "lactate sensor" that keenly detects and binds to free lactic acid to form lactate-AMP under ATP-dependent conditions, and then transfers lactic acid to lysine residues to form lysine lactate groups. There are many targets for AARS1 mediation, and p53 is one of the targets for cancer cells, and the two lysines on the DNA-binding domain of p53 will be lactated, resulting in p53 being unable to bind to response elements, such as p53RE-DNA, and ultimately leading to a decrease in activity.
These findings not only reaffirm the important role of lactate in cancer development, but also bring new directions for cancer treatment, such as the study that b-alanine can competitively bind to AARS1 to prevent the occurrence of p53 lactation, which may be combined with other cancer therapies to enhance the effect of tumor clearance.
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[1] Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis. Cell (2024). DOI: https://doi.org/10.1016/j.cell.2024.04.002