title: A novel role of sodium butyrate in the regulation of cancer-associated aromatase promoters I.3 and II by disrupting a transcriptional complex in breast adipose fibroblasts.
abstract: The aromatase gene encodes the key enzyme for estrogen formation. Aromatase enzyme inhibitors eliminate total body estrogen production and are highly effective therapeutics for postmenopausal breast cancer. A distal promoter (I.4) regulates low levels of aromatase expression in tumor-free breast adipose tissue. Two proximal promoters (I.3/II) strikingly induce in vivo aromatase expression in breast fibroblasts surrounding malignant cells. Treatment of breast fibroblasts with medium conditioned with malignant breast epithelial cells (MCM) or a surrogate hormonal mixture (dibutyryl (Bt2)cAMP plus phorbol diacetate (PDA)) induces promoters I.3/II. The mechanism of promoter-selective expression, however, is not clear. Here we reported that sodium butyrate profoundly decreased MCM- or Bt2cAMP + PDA-induced promoter I.3/II-specific aromatase mRNA. MCM, Bt2cAMP + PDA, or sodium butyrate regulated aromatase mRNA or activity only via promoters I.3/II but not promoters I.1 or I.4 in breast, ovarian, placental, and hepatic cells. Mechanistically, recruitment of phosphorylated ATF-2 by a CRE (-211/-199, promoter I.3/II) conferred inductions by MCM or Bt2cAMP + PDA. Chromatin immunoprecipitation-PCR and immunoprecipitation-immunoblotting assays indicated that MCM or Bt2cAMP + PDA stabilized a complex composed of phosphorylated ATF-2, C/EBPbeta, and cAMP-response element-binding protein (CREB)-binding protein in the common regulatory region of promoters I.3/II. Overall, histone acetylation patterns of promoters I.3/II did not correlate with sodium butyrate-dependent silencing of promoters I.3/II. Sodium butyrate, however, consistently disrupted the activating complex composed of phosphorylated ATF-2, C/EBPbeta, and CREB-binding protein. This was mediated, in part, by decreased ATF-2 phosphorylation. Together, these findings represent a novel mechanism of sodium butyrate action and provide evidence that aromatase activity can be ablated in a signaling pathway- and cell-specific fashion.
authors.affiliation: Division of Reproductive Biology Research, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Santanu
authors.initials: S
authors.lastname: Deb
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.forename: Zhou
authors.initials: Z
authors.lastname: Jianfeng
authors.forename: Sanober A
authors.initials: SA
authors.lastname: Amin
authors.forename: Ayse Gonca
authors.initials: AG
authors.lastname: Imir
authors.forename: Imir Ayse
authors.initials: IA
authors.lastname: Gonca
authors.forename: Mehmet Bertan
authors.initials: MB
authors.lastname: Yilmaz
authors.forename: Yilmaz Mehmet
authors.initials: YM
authors.lastname: Bertan
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lin
authors.forename: Lin
authors.initials: L
authors.lastname: Zihong
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000273:Adipose Tissue; D001141:Aromatase / Q000235:genetics*; D001940:Breast / Q000166:cytology*; D001943:Breast Neoplasms / Q000473:pathology*; D002087:Butyrates / Q000494:pharmacology*; D023081:CCAAT-Binding Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000166:cytology; D046912:Multiprotein Complexes / Q000378:metabolism; D010053:Ovary / Q000166:cytology; D010766:Phosphorylation; D010920:Placenta / Q000166:cytology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D002087:Butyrates; D023081:CCAAT-Binding Factor; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D001141:Aromatase; D050882:CREB-Binding Protein; C494363:CREBBP protein, human