Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance

Cell Discovery

Article

Kui-Sheng Chen¹  Zhi-Li Jiang²  Xing-Yuan Shi²  Chao Cheng³  Wen-You Chen⁴  Can-Can Zheng⁵  Da-Jiang Qin⁵  Xian Wei⁵  Bin Li⁵  Shu-Jun Li⁶  Jing Yang⁶  Guo-Geng Zhang⁶  Tao-Yang Xu⁶  Yan He⁶  Jiao-Jiao Xu⁶  Jin-Bao Liu⁷ 

[1] Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Tumor Pathology, Zhengzhou, Henan, China;Department of Radiation Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;Department of Thoracic Surgery, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China;Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China;Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China;Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China;

关键词: ;   

DOI  :  10.1038/s41421-023-00570-y

 received in 2023-02-17, accepted in 2023-05-24,  发布年份 2023

来源: Springer

【 摘 要 】

Posttranslational modification dramatically enhances protein complexity, but the function and precise mechanism of novel lysine acylation modifications remain unknown. Chemoresistance remains a daunting challenge to successful treatment. We found that lysine butyrylation (Kbu) is specifically upregulated in chemoresistant tumor cells and tissues. By integrating butyrylome profiling and gain/loss-of-function experiments, lysine 754 in HSP90 (HSP90 K754) was identified as a substrate for Kbu. Kbu modification leads to overexpression of HSP90 in esophageal squamous cell carcinoma (ESCC) and its further increase in relapse samples. Upregulation of HSP90 contributes to 5-FU resistance and can predict poor prognosis in cancer patients. Mechanistically, HSP90 K754 is regulated by the cooperation of KAT8 and HDAC11 as the writer and eraser, respectively; SDCBP increases the Kbu level and stability of HSP90 by binding competitively to HDAC11. Furthermore, SDCBP blockade with the lead compound V020-9974 can target HSP90 K754 to overcome 5-FU resistance, constituting a potential therapeutic strategy.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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