title: Role of SUMOylation in full antiestrogenicity.
abstract: The selective estrogen receptor downregulator (SERD) fulvestrant can be used as second-line treatment for patients relapsing after treatment with tamoxifen, a selective estrogen receptor modulator (SERM). Unlike tamoxifen, SERDs are devoid of partial agonist activity. While the full antiestrogenicity of SERDs may result in part from their capacity to downregulate levels of estrogen receptor alpha (ERα) through proteasome-mediated degradation, SERDs are also fully antiestrogenic in the absence of increased receptor turnover in HepG2 cells. Here we report that SERDs induce the rapid and strong SUMOylation of ERα in ERα-positive and -negative cell lines, including HepG2 cells. Four sites of SUMOylation were identified by mass spectrometry analysis. In derivatives of the SERD ICI164,384, SUMOylation was dependent on the length of the side chain and correlated with full antiestrogenicity. Preventing SUMOylation by the overexpression of a SUMO-specific protease (SENP) deSUMOylase partially derepressed transcription in the presence of full antiestrogens in HepG2 cells without a corresponding increase in activity in the presence of agonists or of the SERM tamoxifen. Mutations increasing transcriptional activity in the presence of full antiestrogens reduced SUMOylation levels and suppressed stimulation by SENP1. Our results indicate that ERα SUMOylation contributes to full antiestrogenicity in the absence of accelerated receptor turnover.
authors: Biochemistry Department, Université de Montréal, Montréal, Québec, Canada.
authors: Khalid
authors: K
authors: Hilmi
authors: Nader
authors: N
authors: Hussein
authors: Rodrigo
authors: R
authors: Mendoza-Sanchez
authors: Mohamed
authors: M
authors: El-Ezzy
authors: Houssam
authors: H
authors: Ismail
authors: Chantal
authors: C
authors: Durette
authors: Martine
authors: M
authors: Bail
authors: Maria Johanna
authors: MJ
authors: Rozendaal
authors: Michel
authors: M
authors: Bouvier
authors: Pierre
authors: P
authors: Thibault
authors: James L
authors: JL
authors: Gleason
authors: Sylvie
authors: S
authors: Mader
mesh_terms: D045744:Cell Line, Tumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000077267:Fulvestrant; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D058207:Sumoylation / Q000187:drug effects*
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D000077267:Fulvestrant; D004958:Estradiol