Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance
© 2023. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Cell discovery - 9(2023), 1 vom: 18. Juli, Seite 74 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
He, Yan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 20.07.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1038/s41421-023-00570-y |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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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| 700 | 1 | |a Zheng, Can-Can |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Shu-Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Tao-Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Xian |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Wen-You |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Zhi-Li |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Jiao-Jiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Guo-Geng |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Kui-Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Xing-Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Da-Jiang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jin-Bao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Bin |e verfasserin |4 aut | |
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