title: Transcriptional repression of estrogen receptor α signaling by SENP2 in breast cancer cells.
abstract: Estrogen receptors (ERs) are ligand-activated transcription factors involved in many physiological and pathological processes, including breast cancer. Their activity is fine-tuned by posttranslational modifications, notably sumoylation. In the present study, we investigated the role of the small ubiquitin-related modifier (SUMO) protease, SUMO1/sentrin/suppressor of Mif 2-specific peptidase 2 (SENP2), in the regulation of ERα activity. We first found SENP2 to significantly repress estradiol-induced transcriptional activity in breast cancer cells (MCF7 and T47D). This effect was observed with a reporter plasmid and on endogenous genes such as TFF1 and CTSD, which were shown to recruit SENP2 in chromatin immunoprecipitation experiments. Using glutathione S-transferase pull-down, coimmunoprecipitation and proximity ligation assays, SENP2 was found to interact with ERα and this interaction to be mediated by the amino-terminal region of the protease and the hinge region of the receptor. Interestingly, we demonstrated that ERα repression by SENP2 is independent of its SUMO protease activity and requires a transcriptional repressive domain located in the amino-terminal end of the protease. Using small interfering RNA assays, we evidenced that this domain recruits the histone deacetylase 3 (HDAC3), to be fully active. Furthermore, using both overexpression and knockdown strategies, we showed that SENP2 robustly represses estrogen-dependent and independent proliferation of MCF7 cells. We provided evidence that this effect requires both the proteolytic and transcriptional activities of SENP2. Altogether, our study unravels a new property for a SUMO protease and identifies SENP2 as a classical transcription coregulator.
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, Institut de Recherche en Cancérologie de Montpellier, INSERM, Unité 896, Université Montpellier 1, and Institut régional du Cancer Montpellier, Montpellier (T.N.A., C.T., A.L., V.C., S.J.), F-34298, France; Université Lyon 1 (S.S., A.P., L.C.), F-69000 Lyon, France; INSERM Unité 1052, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5286, Centre de Recherche en Cancérologie de Lyon, Equipe Labellisée, La Ligue, F-69008 Lyon, France; and Institut des Sciences Pharmaceutiques et Biologiques (S.S.), Faculté de Pharmacie de Lyon, Université Lyon 1, F-69000 Lyon, France.
authors.forename: Thiziri
authors.initials: T
authors.lastname: Nait Achour
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Sentis
authors.forename: Catherine
authors.initials: C
authors.lastname: Teyssier
authors.forename: Amandine
authors.initials: A
authors.lastname: Philippat
authors.forename: Annick
authors.initials: A
authors.lastname: Lucas
authors.forename: Laura
authors.initials: L
authors.lastname: Corbo
authors.forename: Vincent
authors.initials: V
authors.lastname: Cavaillès
authors.forename: Stéphan
authors.initials: S
authors.lastname: Jalaguier
mesh_terms: D001943:Breast Neoplasms; D049109:Cell Proliferation; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004958:Estradiol / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D003546:Cysteine Endopeptidases; D004958:Estradiol; D047628:Estrogen Receptor alpha; D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3; C506487:ESR1 protein, human; C501833:SENP2 protein, human