Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis

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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. © 2012 Elsevier Ltd All rights reserved.

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Chou, D. H. C., Holson, E. B., Wagner, F. F., Tang, A. J., Maglathlin, R. L., Lewis, T. A., … Wagner, B. K. (2012). Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chemistry and Biology, 19(6), 669–673. https://doi.org/10.1016/j.chembiol.2012.05.010

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