Work

Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression

Year: 2023

Type: article

Abstract: Protein lysine crotonylation is recently identified as a vital posttranslational modification in cellular processes, particularly through the modification of histones. We demonstrated that lysine crotonylation is a prevalent modification in the cytoplasm and mitochondria, including most enzymes that catalyze intermediate metabolism. 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 were 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. Dynamic crotonylation of metabolic enzymes are involved in regulation of metabolism which coordinated with tumor progression. Interestingly, activation of MTHFD1 by decrotonylaion at Lys354 and Lys553 promotes development of pancreatic cancer by resistance to ferroptosis. Our study reveals that crotonylation represents a major metabolic regulatory mechanism in pancreatic cancer progression. Funding Information: This work was supported by the following: The National Key Research and Development Program of China (2017YFC1308604); National Natural Science Foundation of China (81802903); The Shanghai International Science and Technology Collaboration Program (214907137000). Declaration of Interests: The authors declare no competing interests. Ethical Approval Statement: Animal experiments in this study were approved by the Animal Ethics Committee of Fudan University (201802088S).

Source: Cell Reports

DOI: 10.1016/j.celrep.2023.112666