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

• DOI: 10.1016/j.celrep.2024.114272
• Publication Date: 2024-05-24T17:57:08Z
• Authors: Yun-Chien Chang; Christian Gnann; Raphael R. Steimbach; Florian P. Bayer; Severin Lechner; Amirhossein Sakht...; Miriam Abele; Jana Zecha; Jakob Trendel; Matthew The; Emma Lundberg; Aubry K. Miller; Bernhard Kuster
• Keywords: Histone deacetylase inhibitor; Mechanism of Action; Vorinostat; HDAC10

Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T cell lymphoma (CTCL), peripheral (PTCL), and multiple myeloma, but many aspects of their cellular mechanism action (MoA) substantial toxicity not well understood. To shed more light on how KDACis elicit responses, we systematically measured dose-dependent changes in acetylation, phosphorylation, protein expression response to 21 clinical pre-clinical KDACis. The resulting 862,000 dose-response curves revealed, instance, limited specificity histone (HDAC) 1, 2, 3, 6 inhibitors; strong cross-talk between acetylation phosphorylation pathways; localization most drug-responsive sites intrinsically disordered regions (IDRs); an underappreciated role structure; a shift EP300 abundance the cytoplasm nucleus. This comprehensive dataset serves as resource investigation molecular mechanisms underlying KDACi cells can be interactively explored online ProteomicsDB.