Quantitative Analysis of Histone Deacetylase-1 Selective Histone Modifications by Differential Mass Spectrometry
| العنوان: | Quantitative Analysis of Histone Deacetylase-1 Selective Histone Modifications by Differential Mass Spectrometry |
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| المؤلفون: | Fanyu Meng, Jonathan C. Cruz, Astrid M. Kral, Robert E. Settlage, Victoria M. Richon, Cloud P. Paweletz, Ronald C. Hendrickson, J. Paul Secrist, Roy M. Pollock, Thomas A. Miller, Nathan A. Yates, Anita Y. H. Lee, Nicole Ozerova, Matthew G. Stanton |
| المصدر: | Journal of Proteome Research. 7:5177-5186 |
| بيانات النشر: | American Chemical Society (ACS), 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Proteomics, Spectrometry, Mass, Electrospray Ionization, animal structures, Proteome, Antineoplastic Agents, Biochemistry, Gene Expression Regulation, Enzymologic, Histone Deacetylases, Mass Spectrometry, Histones, Histone H3, In vivo, Cell Line, Tumor, Histone H2B, Humans, Protein Isoforms, False Positive Reactions, Regulation of gene expression, biology, Chemistry, General Chemistry, HDAC1, enzymes and coenzymes (carbohydrates), Histone, ROC Curve, embryonic structures, biology.protein, Histone deacetylase, biological phenomena, cell phenomena, and immunity, Peptides, Chromatography, Liquid |
| الوصف: | Inhibitors of class 1 and class 2 histone deacetylase (HDAC) enzymes have shown antitumor activity in human clinical trials. More recently, there has been interest in developing subtype-selective HDAC inhibitors designed to retain anticancer activity while reducing potential side effects. Efforts have been initiated to selectively target HDAC1 given its role in tumor proliferation and survival. The development of HDAC1-specific inhibitors will require the identification of HDAC1-selective pharmacodynamic markers that correlate closely with HDAC1-inhibition in vitro and in vivo. Existing histone markers of HDAC target engagement were developed using pan-HDAC inhibitors and do not necessarily represent robust readouts for isoform-specific inhibitors. Therefore, we have initiated a proteomic approach to identify readouts for HDAC1 inhibition. This approach involves the use of differential mass spectrometry (dMS) to identify post-translational changes in histones by profiling histone-enriched cellular fractions treated with various HDAC inhibitors. In this study, we profiled histones isolated from the HCT116 human colon cancer cell line that have been treated with compounds from multiple chemical classes that are specific for HDAC1; HDAC1 and 3; and HDAC1, 3, and 6 enzymes. In two independent experiments, we identified 24 features that correlated with HDAC1-inhibition. Among the peptides modulated by HDAC1-selective inhibitors were Ac-H2B-K5 from histone H2B, and Ac-H3-K18 from histone H3. Commercially available antibodies to specific histone acetyl-lysine residues were used to confirm that these peptides also provide pharmacodynamic readouts for HDAC1-selective inhibitors in vivo and in vitro. These results show the utility of dMS in guiding the identification of specific readouts to aid in the development of HDAC-selective inhibitors. |
| تدمد: | 1535-3907 1535-3893 |
| DOI: | 10.1021/pr800510p |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9bb7d272e344e421759a4a6a246ad557 https://doi.org/10.1021/pr800510p |
| رقم الانضمام: | edsair.doi.dedup.....9bb7d272e344e421759a4a6a246ad557 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15353907 15353893 |
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| DOI: | 10.1021/pr800510p |