KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis

• 成果类型: Article
• 署名作者: Xie, Bingteng; Zhang, Mengdi; Li, Jie; Cui, Jianxin; Zhang, Pengju; Liu, Fangming; Wu, Yuxi; Deng, Weiwei; Ma, Jihong; Li, Xinyu; Pan, Bingchen; Zhang, Baohui; Zhang, Hongbing; Luo, Aiqin; Xu, Yinzhe; Li, Mo; Pu, Yang
• 署名单位: Beijing Institute of Technology; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Chinese People's Liberation Army General Hospital; Chinese People's Liberation Army General Hospital; University of Virginia; China Medical University; Chinese People's Liberation Army General Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9575
• DOI: 10.1073/pnas.2314128121
• 发表日期: 2024-02-20
• 关键词: histone acetyltransferase activity; translation elongation; cell-cycle; lactate; inhibition; apoptosis

摘要

Aberrant lysine lactylation (Kla) is associated with various diseases which are caused by excessive glycolysis metabolism. However, the regulatory molecules and downstream protein targets of Kla remain largely unclear. Here, we observed a global Kla abundance profile in colorectal cancer (CRC) that negatively correlates with prognosis. Among lactylated proteins detected in CRC, lactylation of eEF1A2K408 resulted in boosted translation elongation and enhanced protein synthesis which contributed to tumorigenesis. By screening eEF1A2 interacting proteins, we identified that KAT8, a lysine acetyltransferase that acted as a pan-Kla writer, was responsible for installing Kla on many protein substrates involving in diverse biological processes. Deletion of KAT8 inhibited CRC tumor growth, especially in a high- lactic tumor microenvironment. Therefore, the KAT8-eEF1A2 Kla axis is utilized to meet increased translational requirements for oncogenic adaptation. As a lactyltransferase, KAT8 may represent a potential therapeutic target for CRC.