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Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics
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- Chang, Yun Chien (author)
- Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany, Bavaria
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- Gnann, Christian (author)
- KTH,Cellulär och klinisk proteomik,Science for Life Laboratory, SciLifeLab
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- Steimbach, Raphael R. (author)
- Cancer Drug Development, German Cancer Research Center (DKFZ), Heidelberg, Baden-Wurttemberg, Germany, Baden-Württemberg; Biosciences Faculty, Heidelberg University, Heidelberg, Baden-Wurttemberg, Germany, Baden-Württemberg
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- (creator_code:org_t)
- Elsevier BV, 2024
- 2024
- English.
- In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 43:6
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- acetylation
- chemical proteomics
- CP: Molecular biology
- HDACs
- lysine deacetylase inhibitors
- mass spectrometry
- phosphorylation
- proteomic pharmacology
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Chang, Yun Chien
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- Abele, Miriam
- Zecha, Jana
- Trendel, Jakob
- The, Matthew
- Käller Lundberg, ...
- Miller, Aubry K.
- Kuster, Bernhard
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