title: Histone deacetylase inhibitors down-regulate G-protein-coupled estrogen receptor and the GPER-antagonist G-15 inhibits proliferation in endometriotic cells.
abstract: OBJECTIVE
  To investigate whether histone deacetylase inhibitors reduce the expression of the G-protein-coupled estrogen receptor (GPER) and whether the functional inhibition of GPER by the antagonist G-15 decreases the proliferation of endometriotic cells.
  
  
  METHODS
  In vitro study.
  
  
  METHODS
  University hospital.
  
  
  METHODS
  Immortalized epithelial endometriotic cells.
  
  
  METHODS
  Treatment with the histone deacetylase inhibitor romidepsin or suberoylanilide hydroxamic acid (SAHA), or with the GPER antagonist G-15.
  
  
  METHODS
  Western blot analysis and quantitative real-time polymerase chain reaction (PCR) were used to monitor the expression of GPER in response to drug treatment. Effects of GPER stimulation and inhibition on cell proliferation were investigated by the 93-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (Sigma) (MTT) assay.
  
  
  RESULTS
  Our results demonstrate that romidepsin and SAHA reduce GPER expression in a concentration-dependent manner. This reduction correlated with the accumulation of acetylated histones. No decreased expression of the estrogen receptor (ER)-α and ERβ was found under comparable experimental conditions. Pretreatment of endometriotic cells with the GPER agonist G-1 stimulated cell proliferation accompanied by rapid Akt phosphorylation. G-15 reversed this stimulation and inhibited cell proliferation, which was accompanied by Akt dephosphorylation.
  
  
  CONCLUSIONS
  G-protein-coupled estrogen receptor is proposed as a potential therapeutic target in endometriosis. The down-regulation of GPER and/or the impairment of its function may reduce the estrogen responsiveness in endometriosis, and therefore might be considered a possible treatment option of endometriosis.
authors.affiliation: Department of Gynecology, University Hospital Zurich, Zurich, Switzerland. patrick.imesch@usz.ch
authors.forename: Patrick
authors.initials: P
authors.lastname: Imesch
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Samartzis
authors.forename: Konstantin J
authors.initials: KJ
authors.lastname: Dedes
authors.forename: Daniel
authors.initials: D
authors.lastname: Fink
authors.forename: André
authors.initials: A
authors.lastname: Fedier
mesh_terms: D052117:Benzodioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects*; D047630:Depsipeptides / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D004715:Endometriosis / Q000188:drug therapy / Q000473:pathology*; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000077337:Vorinostat
chemical_list: C568862:4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline; D052117:Benzodioxoles; D047630:Depsipeptides; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C109584:GPER1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D000077337:Vorinostat; C087123:romidepsin
keywords: G-15; GPER; endometriosis; estrogen receptors; histone deacetylase inhibitors