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.

翻译后修饰显着增强了蛋白质的复杂性，但新型赖氨酸酰化修饰的功能和精确机制仍然未知。化疗耐药仍然是成功治疗的艰巨挑战。我们发现赖氨酸丁酰化 (Kbu) 在化疗耐药肿瘤细胞和组织中特异性上调。通过整合丁酰组分析和功能获得/丧失实验，HSP90 (HSP90 K754) 中的赖氨酸 754 被确定为 Kbu 的底物。Kbu 修饰导致食管鳞状细胞癌 (ESCC) 中 HSP90 过度表达，并在复发样本中进一步增加。HSP90 的上调会导致 5-FU 耐药，并可预测癌症患者的不良预后。从机制上来说，HSP90 K754 是由 KAT8 和 HDAC11 分别作为写入器和擦除器协同调节的；SDCBP 通过与 HDAC11 竞争性结合来提高 HSP90 的 Kbu 水平和稳定性。此外，用先导化合物V020-9974阻断SDCBP可以靶向HSP90 K754以克服5-FU耐药性，构成一种潜在的治疗策略。