ACSS2-mediated acetate metabolism in endothelial-to-mesenchymal transition and tumor growth

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Credit:DOI: 10.1016/j.cmet.2023.05.010

Acetate metabolism and inflammation are intricately connected in endothelial cells. Zhu et al. revealed a novel pathway by which acetate metabolism controlled endothelial-to-mesenchymal transition (EndMT) and inflammation in endothelial cells, highlighting the importance of modulating acetate metabolism for the treatment of vascular diseases. EndMT is a critical process in the development of chronic vascular diseases like atherosclerosis. EndMT is initiated by the activation of TGF-beta signaling in endothelial cells, which is often triggered by inflammation. Once activated, EndMT leads to increased glucose uptake and glycolysis in endothelial cells. This metabolic shift results in reduced expression of pyruvate dehydrogenase kinase 4 (PDK4), a key inhibitor of the pyruvate dehydrogenase complex (PDH). The decrease in PDK4 activity leads to increased acetate production through the PDH in mitochondria.

The study observed the acetate produced in EndMT was then converted to acetyl-CoA in the cytoplasm by the enzyme acyl-CoA synthase short chain 2 (ACSS2). This process resulted in increased acetylation of TGF-beta signaling proteins, including SMADs 2 and 4, and the TGF-beta receptor ALK5. Acetylation of these proteins enhanced their stability and binding to the ALK5 promoter, leading to increased expression of ALK5 and a subsequent amplification of TGF-beta signaling. This amplified signaling further promoted EndMT, creating a positive feedback loop that perpetuated the process.

These findings suggested that ACSS2 played a pivotal role in this pathway, as its inhibition or knockdown disrupted the positive feedback loop and reversed TGF-beta-induced EndMT. Furthermore, endothelial ACSS2 expression was significantly increased in atherosclerotic lesions in both human and mouse models. This suggested that ACSS2 played a critical role in the development and progression of atherosclerosis.

In conclusion, Zhu et al. demonstrated that TGF-beta signaling, a key driver of EndMT, promoted glucose uptake and glycolysis, leading to increased acetate production. This process was mediated by the enzyme PDK4 inhibition, which enhanced the production of acetate, and the enzyme ACSS2 involvement, which converted acetate to acetyl-CoA in the cytoplasm. Increased acetyl-CoA levels resulted in acetylation of TGF-beta signaling proteins, such as SMAD2/3 and ALK5, which enhanced their stability and nuclear translocation. This, in turn, further promoted TGF-beta signaling, leading to sustained EndMT. Importantly, ACSS2 knockdown in mice inhibited EndMT and reduced atherosclerosis, highlighting its critical role in vascular inflammation. This study provides a new perspective on the role of metabolism in regulating cellular signaling and the pathogenesis of chronic vascular diseases. Further research is needed to fully understand the clinical implications of these findings and to develop targeted therapies for EndMT-related diseases.

Considering the critical role of acetate in remodeling of inflammation responses, another work conducted by Miller et al. investigated the contribution of acetate metabolism in cancer immunotherapy, also with a focus on ACSS2 as a key regulator. Instead of the inhibitory effects exhibited in vascular inflammation, the authors demonstrated that ACSS2 inhibitors or genetic knockout of ACSS2 could enhance antitumor immunity and inhibit tumor growth in breast cancer models. Notably, in immune-competent mice, the normal activation and tumor-suppressing function of immune cells were potentiated by ACSS2 inhibitors, leading to stronger tumor inhibition. Conversely, in immune-deficient mice lacking immune cells, the impact of ACSS2 inhibition on tumor growth was limited.

Mechanistically, knocking down ACSS2 in tumor cells transformed them into acetate providers from consumers, allowing immune cells to use the acetate as a fuel to sustain their functions in the tumor microenvironment. Furthermore, the addition of acetate was shown to enhance T-cell proliferation and function, particularly when glucose was in short supply. The researchers proposed that ACSS2 inhibitors could serve as metabolic immunomodulators by disrupting tumor metabolism and improving immune cell function, a concept that holds promise for cancer therapy. This approach might potentiate antitumor immunity and improve the effectiveness of chemotherapy. However, it is crucial to consider several limitations: the study heavily relied on mouse models, and the results might not be directly applicable to human patients. The role of ACSS2 in innate immunity is yet to be fully understood and warrants future investigation. The broader implications of systemic ACSS2 inhibition on immune responses beyond the tumor microenvironment are not yet fully characterized. Extensive preclinical testing is necessary before the translation of ACSS2 inhibitors into clinical practice.

In summary, these studies offer compelling evidence into the metabolic and immune regulation of atherosclerosis and tumor growth, providing a promising avenue for developing new therapies based on ACSS2 inhibition, which, though requiring additional research, could significantly advance treatment for vascular diseases and cancer.

  1. Zhu X, Wang Y, Soaita I, Lee HW, Bae H, Boutagy N, Bostwick A, Zhang RM, Bowman C, Xu Y, Trefely S, Chen Y, Qin L, Sessa W, Tellides G, Jang C, Snyder NW, Yu L, Arany Z, Simons M. Acetate controls endothelial-to-mesenchymal transition. Cell Metab. 2023 Jul 11;35(7):1163-1178.e10.

  2. Miller KD, O'Connor S, Pniewski KA, Kannan T, Acosta R, Mirji G, Papp S, Hulse M, Mukha D, Hlavaty SI, Salcido KN, Bertolazzi F, Srikanth YVV, Zhao S, Wellen KE, Shinde RS, Claiborne DT, Kossenkov A, Salvino JM, Schug ZT. Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer. Nat Cancer. 2023 Oct;4(10):1491-1507.