Nature Metabolism: Mapping the mastoylation modification of liver cancer tissues

Lactate is the main product of glycolytic metabolism in mammals, and it is significantly increased
in pathological states 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
online on January 2, 2023 in the journal 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 tissues, 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.
Importantly, the analysis of the Kla-modified substrate showed that the modification affects enzymes involved in important metabolic pathways, including glucose metabolism, the tricarboxylic acid (TCA) cycle, 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 HCC.

Figure 1.
Lactation mapping of hepatocellular carcinoma tissues

The research team combined clinical data to dig deep into the data of the lactylation modification group, and found that the Kla level of adenylate kinase 2 (AK2) associated with ATP metabolism in tumor tissues 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.
Functional study of key lactylation sites of AK2

This study systematically mapped the Kla substrate of liver cancer tissues for the first time, revealed that Kla has a broad and key regulatory effect on the metabolism of liver cancer 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, Huanghe Research Group of Shanghai Institute of Materia Medica, and Peng Panpan, master's student, 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
of this paper.
This research was supported
by the National Natural Science Foundation of China and the Shanghai Science and Technology Major Project.

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