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Chem Biol DOI:10.1016/j.chembiol.2012.05.010

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

Publication TypeJournal Article
Year of Publication2012
AuthorsChou, DHung-Chieh, Holson, EB, Wagner, FF, Tang, AJ, Maglathlin, RL, Lewis, TA, Schreiber, SL, Wagner, BK
JournalChem Biol
Date Published2012 Jun 22
KeywordsAnimals, Apoptosis, Benzamides, Cytokines, Dose-Response Relationship, Drug, Glucose, Histone Deacetylase Inhibitors, Histone Deacetylases, Insulin, Insulin-Secreting Cells, Phenylenediamines, Pyridines, Rats, Structure-Activity Relationship, Tumor Cells, Cultured

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.


Alternate JournalChem. Biol.
PubMed ID22726680
PubMed Central IDPMC3383610
Grant ListDP2 DK083048 / DK / NIDDK NIH HHS / United States