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This version published online on July 28, 2005
Molecular Endocrinology, doi:10.1210/me.2005-0178
A more recent version of this article appeared on December 1, 2005
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Submitted on May 3, 2005
Accepted on July 20, 2005

Recruitment of histone deacetylase 4 to the N-terminal region of estrogen receptor alpha

Hoyee Leong, John R. Sloan, Piers D. Nash, and Geoffrey L. Greene*

The Ben May Institute for Cancer Research, The University of Chicago, Chicago, IL 60610

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

Transcriptional activation of estrogen receptor alpha (ER{alpha}) is regulated by the ligand-dependent activation function AF-2 and the constitutively active N-terminal activation function AF-1. To identify ER{alpha} N-terminal-specific coregulators, we screened a breast cDNA library by T7 phage display and isolated histone deacetylase 4 (HDAC4). HDAC4 interacts with the ER{alpha} N-terminus both in vitro and in vivo. Presence of the ER{alpha} DNA binding domain and hinge region reduce HDAC4 recruitment while full length ER{alpha} enhances recruitment. HDAC4 interaction is selective for the ER{alpha} and not ER{beta} N-terminus and occurs in the nucleus. We demonstrate in vivo that HDAC4 is recruited by the N-terminus to the promoter of an endogenous estrogen responsive gene. HDAC4 suppresses transcriptional activation of ER{alpha} by estrogen (E2) and selective ER modulators (SERMs) such as tamoxifen in a cell type-dependent manner. Consistently, silencing of HDAC4 promotes the agonist effect of SERMs (tamoxifen and raloxifene) in a cell type-specific manner. These findings indicate a role for HDAC4 in regulating ER{alpha} activity as a novel N-terminal coregulator and uncover a mechanism by which certain cell types regulate SERM behavior.
Key words: estrogen receptor • histone deacetylase 4 • breast cancer • tamoxifen

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ
Coregulators:   LCoR  |  HDAC4  |  REA  |  HDAC1  |  HDAC2  |  HDAC3  |  MTA1  |  NCOR  |  SMRT
Ligands:   17β-Estradiol  |  Diethylstilbestrol  |  Raloxifene



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