Abstract
Lactyl-coenzyme A (CoA)-dependent histone lysine lactylation impacts gene expression and plays fundamental roles in biological processes. However, mammalian lactyl-CoA synthetases and their regulation of histone lactylation have not yet been identified. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces extracellular signal-regulated kinase (ERK)-mediated S267 phosphorylation of acetyl-CoA synthetase 2 (ACSS2) and its subsequent nuclear translocation and complex formation with lysine acetyltransferase 2A (KAT2A). Importantly, ACSS2 functions as a bona fide lactyl-CoA synthetase and converts lactate to lactyl-CoA, which binds to KAT2A as demonstrated by a co-crystal structure analysis. Consequently, KAT2A acts as a lactyltransferase to lactylate histone H3, leading to the expression of Wnt/β-catenin, NF-κB, and PD-L1 and brain tumor growth and immune evasion. A combination treatment with an ACSS2-KAT2A interaction-blocking peptide and an anti-PD-1 antibody induces an additive tumor-inhibitory effect. These findings uncover ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, and the significance of the ACSS2-KAT2A coupling in gene expression and tumor development.
Overview
- The study investigates the role of lactyl-CoA synthetase and lactyltransferase in gene expression and tumor development. The authors demonstrate that EGFR activation induces S267 phosphorylation of ACSS2 and its subsequent nuclear translocation and complex formation with KAT2A. ACSS2 functions as a lactyl-CoA synthetase and converts lactate to lactyl-CoA, which binds to KAT2A as demonstrated by a co-crystal structure analysis. KAT2A acts as a lactyltransferase to lactylate histone H3, leading to the expression of Wnt/β-catenin, NF-κB, and PD-L1 and brain tumor growth and immune evasion. The study aims to identify the role of lactyl-CoA synthetase and lactyltransferase in gene expression and tumor development and to explore the potential of targeting these proteins for cancer treatment. The hypothesis being tested is that ACSS2 and KAT2A play fundamental roles in gene expression and tumor development and that targeting these proteins can inhibit tumor growth and immune evasion. The methodology used for the experiment includes the use of human cell lines and mouse models of brain tumors. The study identifies ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, and the significance of the ACSS2-KAT2A coupling in gene expression and tumor development. The primary objective of the study is to identify the role of lactyl-CoA synthetase and lactyltransferase in gene expression and tumor development and to explore the potential of targeting these proteins for cancer treatment.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions, specifically the effects of EGFR activation on gene expression and tumor development. The authors found that EGFR activation induces S267 phosphorylation of ACSS2 and its subsequent nuclear translocation and complex formation with KAT2A. ACSS2 functions as a lactyl-CoA synthetase and converts lactate to lactyl-CoA, which binds to KAT2A as demonstrated by a co-crystal structure analysis. KAT2A acts as a lactyltransferase to lactylate histone H3, leading to the expression of Wnt/β-catenin, NF-κB, and PD-L1 and brain tumor growth and immune evasion. The key findings of the study are that ACSS2 and KAT2A play fundamental roles in gene expression and tumor development and that targeting these proteins can inhibit tumor growth and immune evasion. The study also identifies ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, and the significance of the ACSS2-KAT2A coupling in gene expression and tumor development. The study provides evidence for the role of lactyl-CoA synthetase and lactyltransferase in gene expression and tumor development and highlights the potential of targeting these proteins for cancer treatment.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The identification of ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, provides new insights into the mechanisms of gene expression and tumor development. The study also highlights the potential of targeting these proteins for cancer treatment. The study's limitations include the use of human cell lines and mouse models of brain tumors, which may not fully capture the complexity of human tumors. Future research directions could include the use of patient-derived xenografts or clinical trials to further validate the findings and explore the potential of targeting ACSS2 and KAT2A for cancer treatment. The study also suggests that the ACSS2-KAT2A coupling may play a role in other diseases, such as metabolic disorders or neurodegenerative diseases, and future research could explore these possibilities.