title: Regulation of ER alpha signaling pathway in neuronal HN10 cells: role of protein acetylation and Hsp90.
abstract: Estrogen has a variety of neuroprotective effects but the molecular basis of its function is still mainly unclear. Estrogen receptor (ER) signaling is highly dependent on posttranslational modifications and the assembly of coactivator and corepressor complexes. Several proteins involved in ER alpha signaling have recently been found to be acetylated, including ER alpha itself and Hsp90, a key chaperone in the functional regulation of ER alpha. ER alpha complexes also contain histone deacetylases (HDAC) which repress transactivation. Our purpose was to clarify the role of protein acetylation and Hsp90 function in the ERE-mediated ER alpha signaling in neuronal HN10 cells. We observed that increasing protein/histone acetylation status with trichostatin A, a potent HDAC inhibitor, increased the 17beta-estradiol (E2)-induced transactivation of ERE-driven luciferase in non-transfected cells, and even more extensively in pER alpha-transfected cells. E2-induced ERE-driven transactivation was blocked by ICI 182.780. Several ER antagonists, such as raloxifene and tamoxifen, were unresponsive. Valproate, an antiepileptic drug which is recently characterized as a HDAC inhibitor, was also able to potentiate the E2-induced ERE-transactivation. Inhibition of the function of Hsp90 chaperone with geldanamycin strongly inhibited the E2-induced ERE-transactivation. Overexpression of SIRT2 protein deacetylase did not inhibit the acetylation-potentiated ERE-driven transactivation indicating that SIRT2 deacetylase is not involved in ER alpha signaling. Our results reveal that ER alpha signaling is dependent on protein acetylation and epigenetic regulation.
authors.affiliation: Department of Neuroscience and Neurology, University of Kuopio, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Suuronen
authors.forename: Johanna
authors.initials: J
authors.lastname: Ojala
authors.forename: Juha M T
authors.initials: JM
authors.lastname: Hyttinen
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
authors.forename: Anders
authors.initials: A
authors.lastname: Thornell
authors.forename: Sergiy
authors.initials: S
authors.lastname: Kyrylenko
authors.forename: Antero
authors.initials: A
authors.lastname: Salminen
mesh_terms: D000107:Acetylation; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism; D002460:Cell Line; D003609:Dactinomycin / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000378:metabolism; D004054:Diethylstilbestrol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D004965:Estrogen Antagonists / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000378:metabolism; D000077267:Fulvestrant; D017930:Genes, Reporter; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D056565:Sirtuin 2; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014635:Valproic Acid / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047029:Lactams, Macrocyclic; D011500:Protein Synthesis Inhibitors; D020845:Selective Estrogen Receptor Modulators; D003609:Dactinomycin; D000077267:Fulvestrant; C012589:trichostatin A; D003687:Dehydroepiandrosterone; D004958:Estradiol; D014635:Valproic Acid; D004054:Diethylstilbestrol; C474199:SIRT2 protein, human; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases; C001277:geldanamycin