PMID:16051668

Citation	Leong, H, Sloan, JR, Nash, PD and Greene, GL (2005) Recruitment of histone deacetylase 4 to the N-terminal region of estrogen receptor alpha. Mol. Endocrinol. 19:2930-42
Abstract	Transcriptional activation of estrogen receptor alpha (ERalpha) is regulated by the ligand-dependent activation function 2 and the constitutively active N-terminal activation function 1. To identify ERalpha N-terminal-specific coregulators, we screened a breast cDNA library by T7 phage display and isolated histone deacetylase 4 (HDAC4). HDAC4 interacts with the ERalpha N terminus both in vitro and in vivo. Presence of the ERalpha DNA binding domain and hinge region reduce HDAC4 recruitment whereas full-length ERalpha enhances recruitment. HDAC4 interaction is selective for the ERalpha and not ERbeta 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 ERalpha 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 ERalpha activity as a novel N-terminal coregulator and uncover a mechanism by which certain cell types regulate SERM behavior.
Links	PubMed Online version:10.1210/me.2005-0178
Keywords	Amino Acid Sequence; Animals; Cell Nucleus/chemistry; Cell Nucleus/metabolism; Cells, Cultured; Estrogen Receptor alpha/analysis; Estrogen Receptor alpha/metabolism; Estrogens/pharmacology; Gene Library; Histone Deacetylases/analysis; Histone Deacetylases/genetics; Histone Deacetylases/metabolism; Humans; Molecular Sequence Data; Promoter Regions, Genetic; Protein Interaction Mapping; Protein Structure, Tertiary; Repressor Proteins/analysis; Repressor Proteins/genetics; Repressor Proteins/metabolism; Selective Estrogen Receptor Modulators/pharmacology; Tamoxifen/pharmacology; Transcription, Genetic; Transcriptional Activation/drug effects
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