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Estradiol downregulation of the tumor suppressor gene BTG2 requires estrogen receptor‐α and the REA corepressor
Author(s) -
Karmakar Sudipan,
Foster Estrella A.,
Smith Carolyn L.
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24133
Subject(s) - trichostatin a , corepressor , estrogen receptor , cancer research , biology , microbiology and biotechnology , repressor , histone deacetylase , gene expression , histone , cancer , breast cancer , gene , genetics
B ‐cell T ranslocation G ene 2 ( BTG2/TIS21/PC3 ) is an anti‐proliferative tumor suppressor gene whose expression is significantly reduced in breast carcinomas, and in MCF‐7 and T‐47D breast cancer cell lines treated with estradiol (E2). In this study the mechanisms involved in E2 down regulation of BTG2 gene expression were examined. Depletion of ERα by siRNA indicated that the receptor is required for E2 down regulation of BTG2 mRNA levels, and cycloheximide experiments indicated that the effect of E2 on BTG2 expression was independent of intermediary protein synthesis. Chromatin immunoprecipitation analyses revealed that ERα interacts with the BTG2 promoter in a ligand‐independent fashion whereas transfection experiments indicated that ERα's DNA and ligand binding domains are required for E2 repression of BTG promoter activity. Surprisingly, histone deacetylase (HDACs) activity is essential for basal expression as evidenced by trichostatin A inhibition of BTG2 mRNA levels. Estradiol treatment did not alter histone H3 acetylation although it did induce displacement of RNA polymerase II from the BTG2 gene. Depletion of the ER specific corepressor REA ( R epressor of E strogen Receptor A ctivity) significantly abrogated E2‐mediated BTG2 repression. Taken together, our results reveal a requirement of HDAC activity for basal BTG2 expression and the ERα‐REA interaction for estrogen repression of the BTG2 gene. The ability of E2‐bound ERα and REA to suppress BTG2 expression indicates a positive role for this corepressor in regulation of breast cancer cell proliferation. © 2008 Wiley‐Liss, Inc.