Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis.
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.
Chemical Biology Program, Broad Institute, Cambridge, MA 02142, USA.
Danny Hung-Chieh
DH
Chou
Edward B
EB
Holson
Florence F
FF
Wagner
Alicia J
AJ
Tang
Rebecca L
RL
Maglathlin
Timothy A
TA
Lewis
Stuart L
SL
Schreiber
Bridget K
BK
Wagner
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D000099186:Histone Deacetylase 3
D001549:Benzamides; D016207:Cytokines; D005947:Glucose; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D007328:Insulin; D010655:Phenylenediamines; D011725:Pyridines; D000099186:Histone Deacetylase 3; C118739:entinostat; C081895:tacedinaline