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

Transcriptional activation of estrogen receptor alpha (ER alpha) is regulated by the ligand-dependent activation function 2 and the constitutively active N-terminal activation function 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 whereas 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 terminus to the promoter of an endogenous estrogen responsive gene. HDAC4 suppresses transcriptional activation of ER beta 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 alpha activity as a novel N-terminal coregulator and uncover a mechanism by which certain cell types regulate SERM behavior.