Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance

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 upregu...

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Published inCell discovery Vol. 9; no. 1; p. 74
Main Authors He, Yan, Zheng, Can-Can, Yang, Jing, Li, Shu-Jun, Xu, Tao-Yang, Wei, Xian, Chen, Wen-You, Jiang, Zhi-Li, Xu, Jiao-Jiao, Zhang, Guo-Geng, Cheng, Chao, Chen, Kui-Sheng, Shi, Xing-Yuan, Qin, Da-Jiang, Liu, Jin-Bao, Li, Bin
Format Journal Article
LanguageEnglish
Published Singapore Springer Nature Singapore 18.07.2023
Springer Nature B.V
Nature Publishing Group
Subjects
631/1647/2067
631/337/458
631/67/1059/153
631/67/1059/2326
Acylation
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell Cycle Analysis
Cell Physiology
Chemoresistance
Drug resistance
Esophageal cancer
Esophageal carcinoma
Hsp90 protein
Life Sciences
Lysine
Mutation
Proteins
Signal transduction
Squamous cell carcinoma
Stem Cells
Tumor cells
Writers
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Summary: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.
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ISSN:2056-5968
2056-5968
DOI:10.1038/s41421-023-00570-y