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Lactate is the main product of glycolytic metabolism in mammals, and it is significantly increased
in pathological conditions such as tumors, sepsis, and autoimmune diseases.
Its biological function has received widespread attention
due to the "Warburg effect" present in tumor cells.
In 2019, Professor Yingming Zhao's team at the University of Chicago discovered 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 closely related
to 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
its clinical features.
Several scientific questions arise: 1) Does the accumulation of lactic acid in liver cancer tissue drive the formation of mastoylation modifications? 2) Are there a large number of non-histone lactylation modifications? 3) How does lactylation affect the occurrence and development of liver cancer?
In order to explore and solve the above problems, the team of Academician Fan Jia and Professor Gao Qiang of Zhongshan Hospital affiliated to Fudan University and the Yellow River research group of Shanghai Institute of Materia Medica, Chinese Academy of Sciences cooperated to draw the mascylation modification map of liver cancer tissue, and carried out the study
of lactylation function of liver cancer.
The study was published in Nature on January 2, 2023 under the title: Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma Journal of Metabolism.
A total of 52 patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) were collected, and in-depth lactoylation modifier and proteome analysis was performed, and 9275 Kla sites and 9140 proteins were successfully identified (Figure 1).
。 Among them, 9256 lactylation modification sites were located on non-histone proteins, indicating that this modification may involve a wider range of biological functions
in addition to transcriptional regulation.
More importantly, the analysis of Kla-modified substrates showed that the modification affects enzymes involved in important metabolic pathways, including glucose metabolism, tricarboxylic acid (TCA) cycle, amino acid metabolism, fatty acid metabolism, and nucleotide metabolism, and higher Kla levels on proteins in these metabolic pathways are closely related
to the aggressive clinical features and driver mutations of HCC.
Fig.
1.
The research
team combined clinical data to deeply mine the data of the lactylation modification group in the malctocellular carcinoma tissue, and found that the Kla level of adenylate kinase 2 (AK2) associated with ATP metabolism in the tumor tissues of patients with strong proliferative subtype was higher and the prognosis was poor
。 In addition, patients with a higher degree of AK2 lactation were more likely to develop tumor thrombosis, and its carcinogenic signaling pathway, liver-specific metabolism-related pathway and p53 tumor suppression pathway were down-regulated, 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.
Experiments confirmed that lactic acidation at K28 inhibits AK2 kinase activity, leads to intracellular energy disorders, and promotes proliferation, invasion and transfer of HCC cells (Figure 2).
The above results suggest that Kla plays an important role in regulating cellular metabolism and may promote HCC progression
through abnormal metabolism.
Figure 2.
The study of the function of AK2 key lactation sites was the first systematic and comprehensive mapping of Kla substrate in liver cancer tissues, revealing that Kla has extensive and key regulatory effects on the metabolism of hepatoma cells, and verified the function of Kla regulating metabolism-related proteins through experiments, which provided new insights for the course progression and therapeutic intervention of
HCC.
Yang Zijian and Ma Jiaqiang, doctoral students of Zhongshan Hospital affiliated to Fudan University, Yan Cong, and master student Peng Panpan, Huanghe Research Group of Shanghai Institute of Materia Medica, are co-first authors
of the paper.
Professor Gao Qiang of Zhongshan Hospital affiliated to Fudan University and researcher Huang He of Shanghai Institute of Materia Medica, are co-corresponding authors
.
The research was supported
by the National Natural Science Foundation of China and the Shanghai Science and Technology Major Project.
Link to paper: style="color: rgb(136, 136, 136);font-size: 12px;" _mstmutation="1" _istranslated="1">
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