Related Experiment Video
Updated: Jun 25, 2025
Quantification of Site-specific Protein Lysine Acetylation and Succinylation Stoichiometry Using Data-independent Acquisition Mass Spectrometry
Published on: April 4, 2018
Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics
Yun-Chien Chang1, Christian Gnann2, Raphael R Steimbach3
1Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany.
Abstract:
Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), and multiple myeloma, but many aspects of their cellular mechanism of action (MoA) and substantial toxicity are not well understood. To shed more light on how KDACis elicit cellular responses, we systematically measured dose-dependent changes in acetylation, phosphorylation, and protein expression in response to 21 clinical and pre-clinical KDACis. The resulting 862,000 dose-response curves revealed, for instance, limited cellular specificity of histone deacetylase (HDAC) 1, 2, 3, and 6 inhibitors; strong cross-talk between acetylation and phosphorylation pathways; localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs); an underappreciated role of acetylation in protein structure; and a shift in EP300 protein abundance between the cytoplasm and the nucleus. This comprehensive dataset serves as a resource for the investigation of the molecular mechanisms underlying KDACi action in cells and can be interactively explored online in ProteomicsDB.
Insights
Lysine deacetylase inhibitors (KDACis) impact acetylation and phosphorylation pathways, revealing limited specificity and a crucial role in protein structure. This study provides a comprehensive dataset to explore KDACi mechanisms.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Lysine deacetylase inhibitors (KDACis) are approved for treating certain cancers, but their precise cellular mechanisms and toxicity remain unclear.
- Understanding the molecular effects of KDACis is crucial for developing safer and more effective therapies.
Purpose of the Study:
- To systematically investigate the dose-dependent cellular responses to a wide range of KDACis.
- To elucidate the complex interplay between acetylation, phosphorylation, and protein expression changes induced by KDACis.
Main Methods:
- Generated over 862,000 dose-response curves by measuring acetylation, phosphorylation, and protein expression changes.
- Utilized 21 clinical and pre-clinical KDACis in systematic cellular assays.
- Data analysis focused on identifying drug-specific and pathway-wide effects.
Main Results:
- Revealed limited cellular specificity for inhibitors of histone deacetylases (HDAC) 1, 2, 3, and 6.
- Demonstrated significant cross-talk between acetylation and phosphorylation signaling pathways.
- Identified intrinsically disordered regions (IDRs) as key sites for drug-responsive acetylation, highlighting acetylation's role in protein structure.
- Observed shifts in EP300 protein localization between the cytoplasm and nucleus.
Conclusions:
- The study provides a comprehensive dataset and resource for understanding KDACi molecular mechanisms.
- Findings suggest acetylation plays a more significant role in protein structure than previously recognized.
- The data can guide the development of more targeted KDACi therapies with reduced toxicity.
Related Concept Videos
02:04Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein....
02:32Histone Modification
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone...