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.
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.
Deb
Santanu
S
Division of Reproductive Biology Research, Northwestern University, Chicago, Illinois 60611, USA.
Zhou
Jianfeng
J
Jianfeng
Zhou
Z
Amin
Sanober A
SA
Imir
Ayse Gonca
AG
Gonca
Imir Ayse
IA
Yilmaz
Mehmet Bertan
MB
Bertan
Yilmaz Mehmet
YM
Lin
Zhihong
Z
Zihong
Lin
L
Bulun
Serdar E
SE
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
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