Research article
Trichostatin A enhances acetylation as well as protein stability of ERα through induction of p300 protein
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* Corresponding author: Mi-Ock Lee molee@snu.ac.kr
1 College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Kwanak-gu, Seoul 151-742, Republic of Korea
2 Bio-MAX Institute, Seoul National University, San 56-1, Sillim-dong, Kwanak-gu, Seoul 151-742, Republic of Korea
3 Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Sillim-dong, Kwanak-gu, Seoul 151-742, Republic of Korea
Breast Cancer Research 2010, 12:R22 doi:10.1186/bcr2562
Published: 13 April 2010Abstract
Introduction
Trichostatin A (TSA) is a well-characterized histone deacetylase (HDAC) inhibitor. TSA modifies the balance between HDAC and histone acetyltransferase activities that is important in chromatin remodeling and gene expression. Although several previous studies have demonstrated the role of TSA in regulation of estrogen receptor alpha (ERα), the precise mechanism by which TSA affects ERα activity remains unclear.
Methods
Transient transfection was performed using the Welfect-EX™Plus procedure. The mRNA expression was determined using RT-PCR. Protein expression and interaction were determined by western blotting and immunoprecipitation. The transfection of siRNAs was performed using the Oligofectamine™ reagent procedure.
Results
TSA treatment increased acetylation of ERα in a dose-dependent manner. The TSA-induced acetylation of ERα was accompanied by an increased stability of ERα protein. Interestingly, TSA also increased the acetylation and the stability of p300 protein. Overexpression of p300 induced acetylation and stability of ERα by blocking ubiquitination. Knockdown of p300 by RNA interference decreased acetylation as well as the protein level of ERα, indicating that p300 mediated the TSA-induced stabilization of ERα.
Conclusions
We report that TSA enhanced acetylation as well as the stability of the ERα protein by modulating stability of p300. These results may provide the molecular basis for pharmacological functions of HDAC inhibitors in the treatment of human breast cancer.