title: Application of the histone deacetylase inhibitors for the treatment of endometriosis: histone modifications as pathogenesis and novel therapeutic target.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Yufu-shi, Oita, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Kawano
authors.forename: Kaei
authors.initials: K
authors.lastname: Nasu
authors.forename: Haili
authors.initials: H
authors.lastname: Li
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Tsuno
authors.forename: Wakana
authors.initials: W
authors.lastname: Abe
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Takai
authors.forename: Hisashi
authors.initials: H
authors.lastname: Narahara
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D064447:Checkpoint Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D004715:Endometriosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006657:Histones / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D014635:Valproic Acid / Q000627:therapeutic use*; D000077337:Vorinostat
chemical_list: C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010456:Peptides, Cyclic; C102351:apicidin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077337:Vorinostat; D014635:Valproic Acid; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases