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Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance.
- Source :
-
Cell discovery [Cell Discov] 2023 Jul 18; Vol. 9 (1), pp. 74. Date of Electronic Publication: 2023 Jul 18. - Publication Year :
- 2023
-
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.<br /> (© 2023. The Author(s).)
Details
- Language :
- English
- ISSN :
- 2056-5968
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell discovery
- Publication Type :
- Academic Journal
- Accession number :
- 37460462
- Full Text :
- https://doi.org/10.1038/s41421-023-00570-y