Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Chou, DHung-Chieh, Holson, EB, Wagner, FF, Tang, AJ, Maglathlin, RL, Lewis, TA, Schreiber, SL, Wagner, BK |
Journal | Chem Biol |
Volume | 19 |
Issue | 6 |
Pages | 669-73 |
Date Published | 2012 Jun 22 |
ISSN | 1879-1301 |
Keywords | Animals, 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 |
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. |
URL | http://linkinghub.elsevier.com/retrieve/pii/S1074-5521(12)00174-3 |
DOI | 10.1016/j.chembiol.2012.05.010 |
Pubmed | |
Alternate Journal | Chem. Biol. |
PubMed ID | 22726680 |
PubMed Central ID | PMC3383610 |
Grant List | DP2 DK083048 / DK / NIDDK NIH HHS / United States |