IF=20.8|Ubigene’s Point Mutation Cell Lines Help Reveal The Involvement Of Acetate In Tumor Metabolism Reprogramming And New Mechanisms of Immune Evasion

IF=20.8|Ubigene's Point Mutation Cell Lines Help Reveal The Involvement Of Acetate In Tumor Metabolism Reprogramming And New Mechanisms of Immune Evasion 

Acetate is a precursor of acetyl-CoA, playing a crucial role in energy production, lipid synthesis, and protein acetylation. However, it is unknown whether acetate reprograms tumor metabolism and contributes to immune evasion in cancer.

Recently, researchers from Zhejiang University and the Chinese Academy of Medical Sciences and Peking Union Medical College, led by Zhimin Lu and Jie He, published a research paper titled “Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc” on Nature Metabolism (IF: 20.8). This study demonstrated that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissue, with increased acetate uptake as the tumors enriched. The study used Ubigene-constructed MYC (p.K148R) point mutant A549 cells and MYC (p.K148Q) point mutant A549 cells, simulating acetylated and non-acetylated c-Myc states, and investigated the impact of these changes on tumor cell behavior.

Acetyl-CoA derived from acetate induces c-Myc acetylation, mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. To comprehensively understand the function and mechanism of c-Myc acetylation, MYC (p.K148R) A549 cells and MYC (p.K148Q) A549 cells constructed by Ubigene were used to simulate the acetylated and non-acetylated states of c-Myc, investigating the impact of these changes on tumor cell behavior. The research found that acetylated c-Myc increased its stability and subsequently encoded the transcription of genes for PD-L1, glycolytic enzymes, monocarboxylate transporter 1, and cell cycle accelerators. Dietary supplementation of acetate can promote tumor growth and inhibit CD8+ T cell infiltration, while disrupting acetate uptake can inhibit immune evasion, thus improving the efficacy of anti-PD-1 therapy.

Acetate in the blood circulation can be derived from the diet (such as dairy, processed meat and bread, ethanol, and indigestible carbohydrates), the breakdown of dietary fiber by gut microbiota, and acetylated metabolites within the body. Acetate concentrations in human plasma range from 50 μM to 200 μM, and can exceed 800 μM in the plasma of chronic drinkers. Acetate serves as a biological substrate in human tumors. Positron emission tomography (PET) imaging studies using ¹¹C-acetate have shown that prostate, lung, liver, and brain tumor patients exhibit significant acetate uptake, which has advantages in accuracy and sensitivity compared to ¹⁸F-fluorodeoxyglucose PET imaging.

In ¹³C-acetate metabolic tracer studies promoted by nuclear magnetic resonance, patients with glioblastoma, breast cancer, and non-small cell lung cancer (NSCLC) infused with ¹³C-acetate during surgical resection displayed robust acetate oxidation dependent on acetyl-CoA synthetase 2 (ACSS2), which converts acetate and CoA to acetyl-CoA. Additionally, ACSS2 plays an important role in acetate-dependent lipogenesis, histone acetylation, and maintenance of tumor cell growth under metabolic stress. Although acetate has been extensively studied as an energy source and a regulator of gene expression dependent on histone modification, it is still unclear whether it directly regulates oncogenic proteins to mediate tumor growth.

This study demonstrated that NSCLC cells uptake acetate in a manner dependent on Monocarboxylate Transporter 1 (MCT1). Acetyl-CoA derived from acetate and produced through ACSS induces acetylation of c-Myc lysine 148 mediated by dihydrolipoamide S-acetyltransferase (DLAT), recruiting ubiquitin-specific peptidase 10 (USP10) to deubiquitinate and stabilize c-Myc, leading to enhanced programmed death-ligand 1 (PD-L1) expression and promoting tumor immune evasion, as well as the expression of glycolytic and cell cycle progression genes to accelerate cell proliferation.

Figure 1 Mechanism pattern diagram

In summary, these findings emphasize the key role of acetate in promoting tumor growth, not only as a metabolic carbon source, but also through reprogramming tumor metabolism and immune evasion. These findings also highlight the potential of controlling acetate metabolism to inhibit tumor growth and improve the response to immune checkpoint blockade therapy.

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