Application of the histone deacetylase inhibitors for the treatment of endometriosis: histone modifications as pathogenesis and novel therapeutic target

BACKGROUND: Accumulating evidence suggests that various epigenetic aberrations play definite roles in the pathogenesis of endometriosis. We investigated the histone acetylation status in endometriosis and the application of the histone deacetylase inhibitors (HDACIs) for the treatment of endometriosis. METHODS: The levels of acetylated histones in the endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) were evaluated. The effects of the HDACIs on cell proliferation, the cell cycle, apoptosis of ECSCs and NESCs, and the expression of genes related to these cellular events were investigated. The effects of HDACIs on histone acetylation in chromatin of the promoter region of the cell cycle regulatory genes in ECSCs were also investigated. RESULTS: The acetylated histone levels were significantly lower in ECSCs than in NESCs (P < 0.025). HDACIs inhibited cell proliferation and induced cell cycle arrest and apoptosis of ECSCs. The effects of HDACIs on NESCs were marginal or weak. 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 cycle checkpoint kinase 2 genes in ECSCs. HDACIs induced the protein expression of these cell cycle regulators and suppressed the protein expression of Bcl-2 and Bcl-X-L in ECSCs. CONCLUSIONS: The present findings demonstrated that 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 therefore promising agents for the treatment of endometriosis.