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This version published online on March 3, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0011
Molecular Endocrinology Vol. 0, No. 2005 200400111-
doi:10.1210/me.2004-0011
Copyright © 2005 by the Endocrine Society.
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Submitted on January 12, 2004
Accepted on February 22, 2005

Release of Methyl CpG Binding Proteins and Histone Deacetylase 1 from the Estrogen Receptor Alpha (ER) Promoter upon Reactivation in ER-negative Human Breast Cancer Cells

Dipali Sharma, Julie Blum, Xiaowei Yang, Normand Beaulieu, A. Robert Macleod, and Nancy E. Davidson*

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231[DS, JB, XY, NED], and MethylGene Inc, Montreal, Canada H45 2A1 [NB, ARM]

* To whom correspondence should be addressed. E-mail: davidna{at}jhmi.edu.

Estrogen receptor alpha (ER) is an epigenetically regulated gene. Inhibitors of DNA methyltransferases (DNMT) and histone deacetylases (HDAC) synergistically activate the methylated ER gene promoter in ER negative MDA-MB-231 human breast cancer cells. Chromatin immunoprecipitation (ChIP) was used to examine the chromatin status and repressor complex associated with silenced ER and changes in the key regulatory factors during reactivation by inhibitors of DNMT (5-aza-2'deoxycytidine or 5-aza-dC) and HDAC (trichostatin A or TSA). The silencing of ER due to CpG hypermethylation correlates with binding of specific methyl-binding proteins, DNA methyltransferases and HDAC proteins. Inhibition of HDAC activity by TSA results in the accumulation of hyperacetylated core histones. The activation of ER gene expression by 5aza-dC also involves the release of the repressor complex involving various methyl binding proteins, DNMTs, and HDAC1. HDAC and DNMT inhibitors modulate histone methylation at H3-K9 and H3-K4 to form a more open chromatin structure necessary for reactivation of silenced ER transcription. Together these results impart a better understanding of molecular mechanisms of chromatin remodeling during ER reactivation by DNMT and HDAC inhibitors. These findings will aid in the application of agents targeting epigenetic changes in the treatment of breast cancer.
Key words: breast cancer • methyl-CpG binding proteins • histone deacetylase • estrogen receptor

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα
Coregulators:   HDAC1



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