Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China.
Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China; Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission, Minhang Hospital, Fudan University, Shanghai, China.
Cell Rep. 2023 Jul 25;42(7):112666. doi: 10.1016/j.celrep.2023.112666. Epub 2023 Jun 21.
Protein lysine crotonylation has been recently identified as a vital posttranslational modification in cellular processes, particularly through the modification of histones. We show that lysine crotonylation is an important modification of the cytoplastic and mitochondria proteins. Enzymes in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamine metabolism, glutathione metabolism, the urea cycle, one-carbon metabolism, and mitochondrial fusion/fission dynamics are found to be extensively crotonylated in pancreatic cancer cells. This modulation is mainly controlled by a pair of crotonylation writers and erasers including CBP/p300, HDAC1, and HDAC3. The dynamic crotonylation of metabolic enzymes is involved in metabolism regulation, which is linked with tumor progression. Interestingly, the activation of MTHFD1 by decrotonylation at Lys354 and Lys553 promotes the development of pancreatic cancer by increasing resistance to ferroptosis. Our study suggests that crotonylation represents a metabolic regulatory mechanism in pancreatic cancer progression.
蛋白质赖氨酸巴豆酰化最近被鉴定为细胞过程中的一种重要的翻译后修饰，特别是通过组蛋白的修饰。我们表明赖氨酸巴豆酰化是细胞质和线粒体蛋白的重要修饰。糖酵解、三羧酸（TCA）循环、脂肪酸代谢、谷氨酰胺代谢、谷胱甘肽代谢、尿素循环、一碳代谢和线粒体融合/裂变动力学中的酶在胰腺癌细胞中被广泛巴豆酰化。这种调节主要由一对巴豆酰化书写器和橡皮擦控制，包括 CBP/p300、HDAC1 和 HDAC3。代谢酶的动态巴豆酰化参与代谢调节，与肿瘤进展有关。有趣的是，赖氨酸 354 和赖氨酸 553 处的去巴豆酰化激活 MTHFD1 可通过增加对铁死亡的抵抗力促进胰腺癌的发展。我们的研究表明，巴豆酰化代表了胰腺癌进展中的一种代谢调节机制。
