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Tumor cell acetyl coenzyme A synthetase 2 (ACSS2) can use acetic acid and coenzyme A to synthesize acetyl-CoA to provide a carbon source for tumor cell growth. Studies have shown that the expression of ACSS2 is significantly increased in tumor cells, suggesting that ACSS2 is closely related to tumor growth.
ACSS2 is the main protease for acetyl-CoA synthesis in anaerobic bacteria and provides the carbon source needed for anaerobic growth. For example, during the growth and reproduction of yeast, ACSS2 consumes ATP and directly synthesizes acetyl-CoA with acetic acid and coenzyme A, thereby providing carbon sources for various life activities such as ribosome synthesis, protein translation, and amino acid biosynthesis. Since normal mammals can be oxidatively decarboxylated by pyruvate to produce acetyl-CoA during energy metabolism, acetyl-CoA is not dependent on ACSS2. Therefore, ACSS2 is mainly found in some anaerobic bacteria.
Comerford et al. found that only when mammalian cells are under energy stress, the cells choose the metabolic way of glycolysis to provide the ATP required by the cells. At the same time, the pyruvic acid produced by the glycolysis process converts pyruvate into lactic acid and excretes extracellularly under the action of pyruvate dehydrogenase. In the cell, acetyl-CoA loses the source of oxidative decarboxylation of pyruvate, so the expression of ACSS2 in the cell will be increased, thereby directly utilizing the extracellular acetic acid as a raw material to synthesize acetyl-CoA, thereby providing the carbon source required for the normal life of the cell. Xu et al. found that acetic acid levels were significantly increased in human hepatoma cells Hep3B and acute anemia mice, and the expression of ACSS2 was increased. It then promotes the acetylation of hypoxia-inducible factor-2α (HIF-2α) and the formation of CBP-HIF-2α complex protein, thereby promoting the expression of erythropoiesis-related proteins and accelerating the production of red blood cells.
The role of ACSS2 in Tumor Energy Metabolism
Studies have shown that many tissues have an increase in ACSS2 expression and an increase in acetic acid uptake during tumorigenesis and progression. Mashimo et al. measured the uptake of acetic acid and the expression of ACSS2 in tumor cells excised from the brain by 13C-nuclear magnetic resonance (13C-NMR). The results showed that in high metastatic brain tumor cells, acetic acid uptake and ACSS2 expression were significantly higher than normal brain tissue; ACSS2 synthesis of acetyl-CoA provided the carbon source for histone acetylation during tumor proliferation and promoted tumor proliferation and metastasis.
Schug et al. found that the expression level of ACSS2 was higher in 40% of invasive ductal carcinomas. It was confirmed by the liquid chromatograph-mass spectrometer (LC-MS) and other methods that after the expression of ACSS2 was increased, it could directly synthesize acetyl-CoA with acetic acid, thereby promoting tumor growth. Tumor cell growth was inhibited by down-regulating the expression level of ACSS2 by small RNA interference technology. At the same time, it was found through clinical studies that the survival rate of patients with high expression of ACSS2 was significantly lower than that of patients with low expression of ACSS2. Chen et al. showed that the use of ACSS2 inhibitors in breast cancer, ovarian cancer and lung cancer cells in vitro showed that ACSS2 inhibitors significantly inhibited tumor cell proliferation. This suggests that ACSS2 plays an important role in tumor proliferation. When tumor cells are under hypoxia and energy stress, the expression of ACSS2 is increased, accelerating the synthesis of acetyl-CoA by tumor cells, regulating HIF-2 signaling pathway, and promoting tumor metastasis. Therefore, ACSS2 can be used as a biomarker for the clinical detection of tumor malignancy and a potential biological target for clinical treatment of tumors.
Molecular Mechanism of Action of ACSS2 on Tumor Development
Acetyl-CoA plays an important role in the process of tumor energy metabolism, and it is an important carbon source in the normal growth process of cells. Acetyl-CoA in normal cells can be formed by decarboxylation of pyruvate, a product of the glycolysis process. The main mode of glucose metabolism in tumor cells under energy stress is aerobic glycolysis. The metabolic way of aerobic glycolysis of tumor cells dehydrogenates pyruvate during glycolysis to produce lactic acid and excretes lactic acid, which does not provide a precursor for the synthesis of acetyl-CoA for tumor cells.
Lyssiotis et al found that in order to maintain the normal growth of tumor cells, the expression of ACSS2 was elevated, which promoted the uptake of acetic acid by tumor cells, and the consumption of ATP directly synthesized acetic acid into acetyl-CoA. Preliminary studies confirmed that when the tumor cells were under energy stress, the expression of ACSS2 was increased, the acetic acid uptake was increased, and ACSS2 synthesized acetyl-CoA by consuming ATP.
Figure 1. ACSS2 maintains histone acetylation by recapturing acetate released by histone deacetylases. (Bulusu, et al. 2017).
Further studies have found that ACSS2 can not only take up acetic acid outside the tumor cells but also use acetic acid present in the cytoplasm produced by tumor metabolism as a raw material for the synthesis of acetyl-CoA. Jr et al. found that ACSS2 uses acetyl-CoA synthesized by acetic acid to play an important role in tumor proliferation and metastasis. It is a major component of tumor cells that synthesize amino acids, nucleotides, and cell membranes. At the same time, acetyl-CoA can regulate the function and gene expression of related enzymes through histone and non-histone acetylation. Therefore, ACSS2 plays an important role in tumorigenesis and development in tumor cells. The expression level of ACSS2 is closely related to the prognosis of tumor patients.
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