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Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics

ABSTRACT: Lysine deacetylase inhibitors (KDACis) are approved for cutaneous T-cell lymphoma (CTCL) and multiple myeloma. Nevertheless, their mechanisms of action (MoA) remain elusive. To characterize the MoA of these drugs in more detail, we systematically measured dose-dependent changes in protein expression, acetylation, and phosphorylation in response to 21 clinical and pre-clinical KDACis. MV4-11 cells were treated for 6 h with vehicle control and 10 increasing doses of the respective drug (from 100 pM to 30 mM). PTM-carrying and unmodified peptides were analyzed separately by liquid chromatography tandem mass spectrometry (LC-MS/MS) for peptide and protein identification and quantification. Furthermore, time-dependent experiments were carried out for Vorinostat and Panobinostat at their respective pEC50 concentrations from the cell viability data. In an independent experiment, the subcellular proteomes of Panobinostat-treated cells were measured.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Bernhard Kuster

PROVIDER: MSV000093608 | MassIVE | Fri Dec 08 10:19:00 GMT 2023

SECONDARY ACCESSION(S): PXD047659

REPOSITORIES: MassIVE

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Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics

Project description:Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T-cell lymphoma (CTCL) and multiple myeloma. The drugs lead to increasing acetylation levels of histones and other proteins, altered gene expression, and cell death. To characterize the mechanisms of action of these drugs in more detail, we systematically measured dose-dependent drug-induced changes in protein expression, acetylation, and phosphorylation in response to 21 clinical and pre-clinical KDACis. The resulting 872,000 dose-response curves revealed, for instance, poor selectivity of HDAC1, 2, 3, and 6 inhibitors in cells, 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 explored online in ProteomicsDB.

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Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics

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