Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany.
Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden.
Cell Rep. 2024 Jun 25;43(6):114272. doi: 10.1016/j.celrep.2024.114272. Epub 2024 May 24.
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.
赖氨酸去乙酰化酶抑制剂（KDACis）已被批准用于治疗皮肤 T 细胞淋巴瘤（CTCL）、外周 T 细胞淋巴瘤（PTCL）和多发性骨髓瘤，但它们的细胞作用机制（MoA）和显著毒性的许多方面尚未得到很好的理解。为了更深入地了解 KDACis 如何引发细胞反应，我们系统地测量了 21 种临床前和临床 KDACis 对乙酰化、磷酸化和蛋白质表达的剂量依赖性变化。由此产生的 862,000 条剂量反应曲线表明，例如，组蛋白去乙酰化酶（HDAC）1、2、3 和 6 抑制剂的细胞特异性有限；乙酰化和磷酸化途径之间存在强烈的串扰；大多数药物反应性乙酰化位点定位于无规卷曲区域（IDRs）；乙酰化在蛋白质结构中的作用被低估；EP300 蛋白丰度在细胞质和细胞核之间发生转移。这个全面的数据集可作为研究 KDACi 在细胞中作用的分子机制的资源，并可在 ProteomicsDB 中在线进行交互式探索。
