Recruitment of histone deacetylase 4 to the N-terminal region of estrogen receptor alpha.
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.
Leong
Hoyee
H
The Ben May Institute for Cancer Research, The University of Chicago, Center for Integrative Sciences, Room W330, 929 East 57th Street, Chicago, IL 60637, USA.
Sloan
John R
JR
Nash
Piers D
PD
Greene
Geoffrey L
GL
D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D015723:Gene Library; D006655:Histone Deacetylases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects
D047628:Estrogen Receptor alpha; D004967:Estrogens; D012097:Repressor Proteins; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C400300:HDAC4 protein, human; D006655:Histone Deacetylases