Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis |
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Authors: | Chou Danny Hung-Chieh Holson Edward B Wagner Florence F Tang Alicia J Maglathlin Rebecca L Lewis Timothy A Schreiber Stuart L Wagner Bridget K |
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Institution: | Chemical Biology Program, Broad Institute, Cambridge, MA 02142, USA. |
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Abstract: | Cytokine-induced beta-cell apoptosis is important to the etiology of type-1 diabetes. Although previous reports have shown that general inhibitors of histone deacetylase (HDAC) activity, such as suberoylanilide hydroxamic acid and trichostatin A, can partially prevent beta-cell death, they do not fully restore beta-cell function. To understand HDAC isoform selectivity in beta cells, we measured the cellular effects of 11 structurally diverse HDAC inhibitors on cytokine-induced apoptosis in the rat INS-1E cell line. All 11 compounds restored ATP levels and reduced nitrite secretion. However, caspase-3 activity was reduced only by MS-275 and CI-994, both of which target HDAC1, 2, and 3. Importantly, both MS-275 and genetic knockdown of Hdac3 alone were sufficient to restore glucose-stimulated insulin secretion in the presence of cytokines. These results suggest that HDAC3-selective inhibitors may be effective in preventing cytokine-induced beta-cell apoptosis. |
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