title: An estrogen-responsive element-targeted histone deacetylase enzyme has an antiestrogen activity that differs from that of hydroxytamoxifen.
abstract: We showed previously that prolonged treatment of a MCF-7-derived cell line with hydroxytamoxifen (OHT) induces the irreversible silencing of some estrogen-responsive genes, whereas OHT-resistant cell growth appears simultaneously (E. Badia et al., Cancer Res., 60: 4130-4138, 2000). Based on the hypothesis that particular gene silencings could be involved in triggering the resistance phenomenon, we focused our study on the mechanism of OHT-induced silencing. More precisely, we wished to determine to what extent the recruited histone deacetylase (HDAC) activity, which is known to be involved in the repressive effect induced by antagonist ligands of nuclear receptors, could participate in various aspects of OHT effects, particularly in gene silencing. A fusion protein (HDAC-EG) of human HDAC1 fused with the estrogen receptor DNA-binding domain and the glucocorticoid receptor ligand-binding domain allowed targeting of chimeric HDAC1 activity on estrogen-responsive elements (EREs) in the presence of glucocorticoid ligands. When HDAC-EG was transiently expressed in HeLa cells together with estrogen receptor, an antiestrogen-like effect was obtained on an ERE-controlled luciferase reporter gene in the presence of agonist or antagonist glucocorticoids. In MCF-7-derived cells stably expressing HDAC-EG and an estrogen-regulated luciferase, liganded HDAC-EG again produced an antiestrogenic effect on expression of natural estrogen-regulated genes such as pS2, progesterone receptor, and cathepsin D and cell growth together with chimeric luciferase gene expression. However, a prolonged HDAC-EG-mediated antiestrogen effect did not lead to irreversible luciferase gene silencing, as OHT does. It nevertheless accelerated the OHT-driven phenomenon. The antiestrogen effect of OHT thus differs from that of an ERE-targeted HDAC1 activity that might participate in irreversible silencing but is not sufficient to trigger it.
authors.affiliation: INSERM U439, 34090 Montpellier, France.
authors.forename: Ediz
authors.initials: E
authors.lastname: Demirpence
authors.forename: Abdelhabib
authors.initials: A
authors.lastname: Semlali
authors.forename: Joan
authors.initials: J
authors.lastname: Oliva
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.forename: Eric
authors.initials: E
authors.lastname: Badia
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Duchesne
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Nicolas
authors.forename: Michel
authors.initials: M
authors.lastname: Pons
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D017930:Genes, Reporter; D006367:HeLa Cells; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020218:Response Elements / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; C016601:afimoxifene; D008156:Luciferases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases