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

Chem Biol
Authors
Keywords
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.

Year of Publication
2012
Journal
Chem Biol
Volume
19
Issue
6
Pages
669-73
Date Published
2012 Jun 22
ISSN
1879-1301
URL
DOI
10.1016/j.chembiol.2012.05.010
PubMed ID
22726680
PubMed Central ID
PMC3383610
Links
Grant list
DP2 DK083048 / DK / NIDDK NIH HHS / United States