title: CCAAT/enhancer-binding protein α is epigenetically silenced by histone deacetylation in endometriosis and promotes the pathogenesis of endometriosis.
abstract: BACKGROUND
  Accumulating evidence suggests that various epigenetic aberrations play definite roles in the pathogenesis of endometriosis.
  
  
  OBJECTIVE
  The objective of the study was to determine the epigenetically silenced genes by histone deacetylation in endometriosis.
  
  
  METHODS
  Histone deacetylase-1 target mRNAs that were up-regulated by valproic acid (VPA) treatment in endometriotic cyst stromal cells (ECSCs) were identified by a global mRNA microarray technique.
  
  
  RESULTS
  We identified 5 candidate genes and chose CCAAT/enhancer-binding protein α (C/EBPα) for further functional experiments. C/EBPα mRNA and protein expression is attenuated in ECSCs, and the expression was up-regulated by VPA stimulation. Immunohistochemical stainings also confirmed the decreased staining for C/EBPα protein in endometriotic tissues. VPA treatment resulted in an accumulation of acetylated histones H3 and H4 in the promoter region of the C/EBPα gene in ECSCs. The compulsory expression of C/EBPα in ECSCs directed the inhibition of cell proliferation and the induction of apoptosis. C/EBPα knockdown by small interfering RNA directed the stimulation of cell proliferation and the resistance to apoptosis in normal eutopic endometrial stromal cells. The expressions of peroxisome proliferator-activated receptor-γ (PPARγ), period homolog 2 (PER2), p53, apoptosis-inducing factor, mitochondrion-associated 1 (AIFM1), Bax, caspase-8, caspase-10, p16(INK4a), p21(Waf1/Cip1), cyclin-dependent kinase (cdk) 2, and cdk4 were down-regulated by C/EBPα knockdown.
  
  
  CONCLUSIONS
  Our findings suggest that an epigenetically suppressed tumor suppressor gene is involved in the pathogenesis of endometriosis by creating the proliferative, antiapoptotic, and other disease-specific characteristics of endometriosis. The results also suggest that histone deacetylase inhibitors are promising agents for the treatment of endometriosis.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Kawano
authors.forename: Kaei
authors.initials: K
authors.lastname: Nasu
authors.forename: Naoki
authors.initials: N
authors.lastname: Hijiya
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsukamoto
authors.forename: Kohei
authors.initials: K
authors.lastname: Amada
authors.forename: Wakana
authors.initials: W
authors.lastname: Abe
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kai
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Moriyama
authors.forename: Hisashi
authors.initials: H
authors.lastname: Narahara
mesh_terms: D000107:Acetylation; D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics* / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D004715:Endometriosis / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D010049:Ovarian Diseases / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D022763:CCAAT-Enhancer-Binding Protein-alpha; D006657:Histones; C421902:PER2 protein, human; D047495:PPAR gamma; D056950:Period Circadian Proteins; D051028:bcl-2-Associated X Protein; D014635:Valproic Acid; D020169:Caspases