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Trichostatin A epigenetically increases calpastatin expression and inhibits calpain activity and calcium‐induced SH ‐ SY 5 Y neuronal cell toxicity
Author(s) -
Seo Jungwon,
Jo Sangmee Ahn,
Hwang Soojin,
Byun Catherine Jeonghae,
Lee HyeonJu,
Cho DuHyong,
Kim Dueon,
Koh Young Ho,
Jo Inho
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12572
Subject(s) - calpastatin , calpain , ionomycin , trichostatin a , sh sy5y , microbiology and biotechnology , chemistry , histone deacetylase , biology , calcium , histone , biochemistry , cell culture , neuroblastoma , enzyme , genetics , organic chemistry , gene
Calpains are involved in calcium‐induced neuronal cell toxicity, which is associated with the pathophysiology of A lzheimer's disease ( AD ). The activity of calpains is regulated by the inhibitor calpastatin, and increased activity of calpains and decreased calpastastin are often found in AD . Histone deacetylase ( HDAC ) inhibitors are implicated in AD treatment through the improvement of learning and memory but the underlying mechanism is yet to be understood. Here, using SH ‐ SY5Y neuroblastoma cells and a calcium ionophore ionomycin, we examined whether and how HDAC inhibitor trichostatin A ( TSA ) inhibits calcium‐induced neuronal cell death. TSA increased both the m RNA and protein levels of calpastatin, with no alterations in those of calpain 1 and calpain 2. Furthermore, TSA ‐stimulated increase of calpastatin was accompanied by a significant attenuation of ionomycin‐induced autolysis of calpain 1, but not of calpain 2, and calpain‐dependent 150 kDa αII spectrin cleavage. Under these conditions, however, caspase activity was unaltered. Moreover, ectopic expression of small interfering RNA of calpastatin reversed the inhibitory effect of TSA on ionomycin‐induced calpain 1 autolysis and αII spectrin cleavage. Chromatin immunoprecipitation assay revealed the increased levels of acetylation at lysine 5 of histone H 4 ( H 4 K 5‐ A c), H 3 K 9‐ A c and H 3 K 14‐ A c within the calpastatin promoter region in TSA ‐treated cells relative to control cells. Finally, TSA significantly decreased ionomycin‐induced cell toxicity. This study demonstrates that TSA attenuates calcium‐induced neuronal cell death by the inhibition of calpain activity which is mediated in part by increased calpastatin expression via histone hyperacetylation within the calpastatin promoter region. Our study provides a novel mechanism for the neuroprotective effect of HDAC inhibitors on AD .