Androgen receptor regulates nuclear trafficking and nuclear domain residency of corepressor HDAC7 in a ligand-dependent fashion.
In addition to chromosomal proteins, histone deacetylases (HDACs) target transcription factors in transcriptional repression. Here, we show that the class II HDAC family member HDAC7 is an efficient corepressor of the androgen receptor (AR). HDAC7 resided in the cytoplasm in the absence of AR or a cognate ligand, but hormone-occupancy of AR induced nuclear transfer of HDAC7. Nuclear colocalization pattern of AR and HDAC7 was dependent on the nature of the ligand. In the presence of testosterone, a portion of HDAC7 localized to pearl-like nuclear domains, whereas AR occupied with antagonistic ligands cyproterone acetate- or casodex (bicalutamide) recruited HDAC7 from these domains to colocalize with the receptor in speckles and nucleoplasm in a more complete fashion. Ectopic expression of PML-3 relieved the repressive effect of HDAC7 on AR function by sequestering HDAC7 to PML-3 domains. AR acetylation at Lys630/632/633 was not the target of HDAC7 repression, since repression of AR function was independent of these acetylation sites. Moreover, the deacetylase activity of HDAC7 was in part dispensable in the repression of AR function. In sum, our results identify HDAC7 as a novel AR corepressor whose subcellular and subnuclear compartmentalization can be regulated in an androgen-selective manner.
Karvonen
Ulla
U
Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, PO Box 63, FI-00014 Helsinki, Finland.
Jänne
Olli A
OA
Palvimo
Jorma J
JJ
D000107:Acetylation / Q000187:drug effects; D000728:Androgens; D050882:CREB-Binding Protein / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D017373:Cyproterone Acetate / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008024:Ligands; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D021381:Protein Transport; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D016385:TATA Box / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C410798:AR protein, human; D000728:Androgens; D006877:Hydroxamic Acids; D008024:Ligands; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D011944:Receptors, Androgen; D012097:Repressor Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C012589:trichostatin A; D017373:Cyproterone Acetate; D050882:CREB-Binding Protein; C543273:HDAC7 protein, human; D006655:Histone Deacetylases