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.

Details

Title
Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance
Author
He, Yan 1 ; Zheng, Can-Can 2 ; Yang, Jing 1 ; Li, Shu-Jun 1 ; Xu, Tao-Yang 1 ; Wei, Xian 2 ; Chen, Wen-You 3 ; Jiang, Zhi-Li 4 ; Xu, Jiao-Jiao 1 ; Zhang, Guo-Geng 1 ; Cheng, Chao 5 ; Chen, Kui-Sheng 6 ; Shi, Xing-Yuan 4 ; Qin, Da-Jiang 2 ; Liu, Jin-Bao 7   VIAFID ORCID Logo  ; Li, Bin 2 

1  The Fifth Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, Guangzhou, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072); Jinan University, MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Guangzhou, China (GRID:grid.258164.c) (ISNI:0000 0004 1790 3548) 
2  The Fifth Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, Guangzhou, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072) 
3  The First Affiliated Hospital of Jinan University, Department of Thoracic Surgery, Guangzhou, China (GRID:grid.412601.0) (ISNI:0000 0004 1760 3828) 
4  The Fifth Affiliated Hospital of Guangzhou Medical University, Department of Radiation Oncology, Guangzhou, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072) 
5  Sun Yat-sen University First Affiliated Hospital, Department of Thoracic Surgery, Guangzhou, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X) 
6  The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Tumor Pathology, Department of Pathology, Zhengzhou, China (GRID:grid.412633.1) (ISNI:0000 0004 1799 0733) 
7  Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072) 
Pages
74
Publication year
2023
Publication date
2023
Publisher
Springer Nature B.V.
e-ISSN
20565968
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41421-023-00570-y
ProQuest document ID
2838512939
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.