| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2011: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2010: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2009: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2008: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
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| Research Abstract |
Accumulating evidences suggest that various epigenetic aberrations play definite roles in the pathogenesis of endometriosis, an estrogen-dependent, tumor-like disease. The aim of this study is to investigate the histone acetylation status in endometriosis and the application of the histone deacetylase inhibitors(HDACIs) for the treatment of endometriosis.
The levels of acetylated histones in the cultured human endometriotic cyst stromal cells(ECSCs) and normal endometrial stromal cells(NESCs) were evaluated. The effects of valproic acid(VPA), suberoyl anilide bishydroxamine(SAHA), and apicidin, on the cell proliferation, cell cycle, apoptosis of ECSCs and NESCs, and the expression of genes related to these cellular events were investigated. The effects of HDACIs on the histone acetylation in the chromatin of the promoter region of the p16^<INK4a>, p21^<Waf1/Cip1>, p27^<Kip1>, and cell cycle checkpoint kinase2(chk2) genes in ECSCs were also investigated.
The acetylated histone H3 and H4 protein levels were significantly lower in unstimulated ECSCs than in NESCs. VPA, SAHA, and apicidin inhibited the cell proliferation, and induced cell cycle arrest and apoptosis of ECSCs. The effects of these HDACIs on NESCs were marginal or weak in comparison with those on ECSCs. These HDACIs induced an accumulation of acetylated histones in total cellular chromatin and in the promoter regions of the p16^<INK4a>, p21^<Waf1/Cip1>, p27^<Kip1>, and chk2genes in ECSCs. HDACIs induced the protein expression of p16^<INK4a>, p21^<Waf1/Cip1>, p27^<Kip1>, and chk2, and suppressed the protein expression of Bcl-2and Bcl-X_L in ECSCs.
The present findings demonstrated that the aberrant histone modifications are present in endometriosis and that HDACIs reactivated epigenetically silenced genes, resulting in the suppression of cell proliferation, induction of cell cycle arrest and apoptosis of ECSCs. HDACIs are considered as promising agents for the treatment of endometriosis.
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