Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics
Yun-Chien Chang,
Christian Gnann,
Raphael R. Steimbach,
Florian P. Bayer,
Severin Lechner,
Amirhossein Sakhteman,
Miriam Abele,
Jana Zecha,
Jakob Trendel,
Matthew The,
Emma Lundberg,
Aubry K. Miller,
Bernhard Kuster
Affiliations
Yun-Chien Chang
Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany
Christian Gnann
Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden
Raphael R. Steimbach
Cancer Drug Development, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany; Biosciences Faculty, Heidelberg University, Heidelberg, Baden-Württemberg, Germany
Florian P. Bayer
Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany
Severin Lechner
Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany
Amirhossein Sakhteman
Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany
Miriam Abele
Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany; Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany
Jana Zecha
Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany
Jakob Trendel
Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany
Matthew The
Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany
Emma Lundberg
Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden; Department of Bioengineering, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA
Aubry K. Miller
Cancer Drug Development, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Baden-Württemberg, Germany
Bernhard Kuster
Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany; Corresponding author
Summary: 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.
