YAP delactylation enhances therapy resistance in renal cell carcinoma
Abstract
Abstract Lactylation is a novel lysine acylation modification, and its function and exact mechanisms remain unclear. The responsiveness to combined targeted and immunotherapy continues to be a major challenge in cancer treatment. Here, we discovered that lysine lactylation (Kla) is specifically downregulated in targeted therapy-resistant renal cancer cells and tissues. The lactylation status of YAP at lysine 90 (K90) regulates its nuclear translocation, which is critical for the expression of epithelial-mesenchymal transition (EMT)-related genes and the PD-L1 gene. Furthermore, we identified HDAC1 as the “eraser” of YAP-K90 lactylation. By transfecting YAP-K90T (a lactylation mimic), we enhanced antitumor immune activity. In xenograft models established in huCD34 + HSC NCG mice, we consistently found that HDAC1 inhibition enhances the response to combination therapy by increasing YAP lactylation and promoting CD8⁺ T cell tumor infiltration. These findings reveal lactylation as a key mechanism in targeted drug response and identify inhibiting YAP delactylation as a promising strategy for renal cell carcinoma treatment.
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Authors: Mingjie Lin, Xiaohan Jin, Minyu Chen, Liangmin Fu, Kun Ye, Yong Huang, Peixian Liang, Lei Tan, Xinwei Zhou, Jinchen Luo, Guannan Shu, Yuhang Chen, Gaosheng Yao, Hansen Lin, Zhu Wang, Qiong Deng, Wei Chen, Junhang Luo, Jiefeng Yang, Hui Liang, Jinhuan Wei
Institutions: Sun Yat-sen University, Central South University, Nanfang Hospital, Southern Medical University, Guangzhou Medical University, Second Affiliated Hospital of Guangzhou Medical University, The First Affiliated Hospital, Sun Yat-sen University, Longgang Central Hospital, Second Xiangya Hospital of Central South University, Guangzhou University of Chinese Medicine, Guangzhou Women and Children Medical Center, Tianjin Medical University Cancer Institute and Hospital, State Key Laboratory of Respiratory Disease, The Seventh Affiliated Hospital of Sun Yat-sen University, ShenZhen People’s Hospital, Guangzhou Chest Hospital