Scientists map lactylation modifications in liver cancer tissues

Lactate is the main product of mammalian glycolytic metabolism, which has increased significantly in pathological states such as tumors, sepsis, and autoimmune diseases, and its biological function has attracted attention due to the “Warburg effect” in tumor cells. In 2019, the team of Professor Yingming Zhao of the University of Chicago in the United States found that lactic acid in mammalian cells can drive the formation of a novel histone post-translational modification (PTM), lysine lactylation (Kla), which in turn plays an important gene transcription regulatory function, thus proposing new insights into the non-metabolic function of lactic acid.

As one of the key organs of glycolipid metabolism, various lesions of the liver are associated with metabolic abnormalities. The large amount of lactic acid accumulated in the cells of hepatocellular carcinoma (HCC) due to the Waberg effect has become one of the clinical features. Several scientific questions arise: Does the accumulation of lactic acid in liver cancer tissue drive the formation of lactic acylation modifications? Are there significant amounts of non-histone lactylation modifications? How does lactylation affect the occurrence and development of liver cancer?

In order to explore and solve the above problems, Fan Jia, academician of the Chinese Academy of Sciences and professor of Zhongshan Hospital affiliated to Fudan University, and Professor Gao Qiang’s team, together with the research group of Huang He, a researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, drew a mastoylation modification map of liver cancer tissues and carried out research on the lactylation function of liver cancer. On January 2, the research results were published online in Nature Metabolism under the title Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma.

A total of 52 patients with hepatitis B virus (HBV)-associated HCC were collected from cancer and paracancerous tissue, and in-depth lactoylation modifier and proteome analysis was performed, identifying 9275 Kla sites and 9140 proteins (Figure 1). Among them, 9256 lactylation modification sites were located on non-histone proteins, indicating that this modification may be involved in a broader biological function in addition to transcriptional regulation. Importantly, the analysis of the Kla-modified substrate showed that the modification affects enzymes involved in important metabolic pathways, including glucose metabolism, tricarboxylic acid (TCA) cycling, amino acid metabolism, fatty acid metabolism, and nucleotide metabolism, and that higher Kla levels on proteins in these metabolic pathways are strongly associated with aggressive clinical features and driver mutations of HCCs.

Figure 1.Lactation map of hepatocellular carcinoma tissue

The scientific research team combined clinical data to dig deep into the data of the lactylation modification group and found that the Kla level of ATP metabolism-related adenylate kinase 2 (AK2) in the tumor tissues of patients with strong proliferative subtypes was higher and the prognosis was poor. In addition, patients with higher degree of AK2 lactation were more likely to develop tumor thrombosis, and its carcinogenic signaling pathway, liver-specific metabolism-related pathway and p53 anticarptic pathway were downregulated, suggesting the underlying mechanism of AK2 lactation and poor prognosis in patients with liver cancer. In order to further explore the specific regulatory mechanism of lactated AK2 affecting HCC, a series of cellular-level experiments were performed. Lactic acidification at K28 confirmed that kinase activity of AK2 was inhibited, leading to intracellular energy disturbance and promoting proliferation, invasion, and metastasis of HCC cells (Figure 2). The above studies suggest that Kla plays an important role in regulating cellular metabolism and may promote HCC progression through abnormal metabolism.

Figure 2. Functional study of key lactylation sites of AK2

This study is the first to systematically and comprehensively map the Kla substrate of liver cancer tissues, revealing that Kla has a broad and key regulatory effect on the metabolism of liver cancer cells, and verifying the function of Kla regulating metabolism-related proteins through experiments, which provides new insights for the disease progression and therapeutic intervention of HCC. The research work is supported by the National Natural Science Foundation of China and the Shanghai Science and Technology Major Project. (Source: Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

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