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Recruitment of Histone Deacetylase 4 to the N-Terminal Region of Estrogen Receptor

The Ben May Institute for Cancer Research, The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Geoffrey L. Greene, The Ben May Institute for Cancer Research, The University of Chicago, Center for Integrative Sciences, Room W330, 929 East 57th Street, Chicago, Illinois 60637. E-mail: ggreene{at}uchicago.edu.

Transcriptional activation of estrogen receptor (ER) is regulated by the ligand-dependent activation function 2 and the constitutively active N-terminal activation function 1. To identify ER 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 N terminus both in vitro and in vivo. Presence of the ER DNA binding domain and hinge region reduce HDAC4 recruitment whereas full-length ER enhances recruitment. HDAC4 interaction is selective for the ER and not ERß 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 by estrogen 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 activity as a novel N-terminal coregulator and uncover a mechanism by which certain cell types regulate SERM behavior.

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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