Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance

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; Bin Li

doi:10.1038/s41421-023-00570-y

Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance

Cell Discov. 2023 Jul 18;9(1):74. doi: 10.1038/s41421-023-00570-y.

Authors

Yan He^#^{1

2}, Can-Can Zheng^#¹, Jing Yang^#^{1

2}, Shu-Jun Li^#^{1

2}, Tao-Yang Xu^{1

2}, Xian Wei¹, Wen-You Chen³, Zhi-Li Jiang⁴, Jiao-Jiao Xu^{1

2}, Guo-Geng Zhang^{1

2}, Chao Cheng⁵, Kui-Sheng Chen⁶, Xing-Yuan Shi⁴, Da-Jiang Qin¹, Jin-Bao Liu⁷, Bin Li⁸

Affiliations

¹ Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
² MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China.
³ Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
⁴ Department of Radiation Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
⁵ Department of Thoracic Surgery, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China.
⁶ Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Tumor Pathology, Zhengzhou, Henan, China.
⁷ Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
⁸ Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. lib2128@163.com.

^# Contributed equally.

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.

Abstract

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