[Molecular mechanism of inhibition of sodium butyrate on activation of tumor associated aromatase promoters].
OBJECTIVE
Sodium butyrate, a histone deacetylase inhibitor, can inhibit tumor conditioned medium-induced levels of promoter II and I. 3-specific transcripts. This study was designed to investigate the action of sodium butyrate on promoter II and I. 3 activity, which can be directed to elucidation of local estrogen production in breast cancer.


METHODS
Primary human adipose fibroblasts (HAF) treated with MCF-7 breast cancer cell-conditioned medium were used as a cell model system. Promoter II and I. 3 deletion luciferase constructs was transfected into HAF. Western blotting and electrophoretic mobility shift assay were performed to evaluate the effect of sodium butyrate on promoter II and I .3.


RESULTS
Breast cancer cell-conditioned medium enhanced phosphorylation of activator transcription factor-2 (ATF-2) which was the main modulatory subtype in CREB/ATF-2 family. The effect of sodium butyrate on aromatase expression in breast tumor fibroblasts was mediated by inhibition of phosphorylation of ATF-2, and hence, the inhibition of binding of a transcriptional complex containing phosphorylated ATF-2, C/EBP beta and CREB binding protein (CBP) to promoter II/I. 3 regulatory region.


CONCLUSIONS
Sodium butyrate reduces the level of aromatase mRNA arising from cancer-induced promoter region. The aberrant activation of promoter II and I. 3 in HAF is dependent on the phosphorylation of ATF-2.
Zhou
Jian-feng
JF
Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, P. R. China. z88hjf@hotmail.com
Liu
Wen-li
WL
Chen
Gang
G
Lu
Yun-ping
YP
Ma
Ding
D
D051697:Activating Transcription Factor 1; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002087:Butyrates / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D012964:Sodium / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D051697:Activating Transcription Factor 1; D002087:Butyrates; D022782:CCAAT-Enhancer-Binding Protein-beta; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014157:Transcription Factors; D012964:Sodium; D001141:Aromatase