1. Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance
- Author
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Yan He, Can-Can Zheng, Jing Yang, Shu-Jun Li, Tao-Yang Xu, Xian Wei, Wen-You Chen, Zhi-Li Jiang, Jiao-Jiao Xu, Guo-Geng Zhang, Chao Cheng, Kui-Sheng Chen, Xing-Yuan Shi, Da-Jiang Qin, Jin-Bao Liu, and Bin Li
- Subjects
Cytology ,QH573-671 - Abstract
Abstract 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.
- Published
- 2023
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