PMID:16120611

Citation	Chen, G, Nomura, M, Morinaga, H, Matsubara, E, Okabe, T, Goto, K, Yanase, T, Zheng, H, Lu, J and Nawata, H (2005) Modulation of androgen receptor transactivation by FoxH1. A newly identified androgen receptor corepressor. J. Biol. Chem. 280:36355-63
Abstract	Androgen signaling plays key roles in the development and progression of prostate cancer, and numerous ongoing studies focus on the regulation of androgen receptor (AR) transactivity to develop novel therapies for the treatment of androgen-independent prostate cancer. FoxH1, a member of the Forkhead-box (FOX) gene family of transcription factors, takes part in mediating transforming growth factor-beta/activin signaling through its interaction with the Smad2.Smad4 complex. Using a series of experiments, we found that FoxH1 repressed both ligand-dependent and -independent transactivation of the AR on androgen-induced promoters. This action of FoxH1 was independent of its transactivation capacity and activin A but relieved by Smad2.Smad4. In addition, the repression of the AR by FoxH1 did not require deacetylase activity. A protein-protein interaction was identified between the AR and FoxH1 independently of dihydrotestosterone. Furthermore, a confocal microscopic analysis of LNCaP cells revealed that the interaction between the AR and FoxH1 occurred in the nucleus and that FoxH1 specifically blocked the foci formation of dihydrotestosterone-activated AR, which has been shown to be correlated with the AR transactivation potential. Taken together, our results indicate that FoxH1 functions as a new corepressor of the AR. Our observations not only strengthen the role of FoxH1 in AR-mediated transactivation but also suggest that therapeutic interventions based on AR-coregulator interactions could be designed to block both androgen-dependent and -independent growth of prostate cancer.
Links	PubMed Online version:10.1074/jbc.M506147200
Keywords	Activins/metabolism; Animals; Blotting, Western; COS Cells; Cell Line, Tumor; Cell Nucleus/metabolism; Cercopithecus aethiops; Dihydrotestosterone/pharmacology; Dose-Response Relationship, Drug; Forkhead Transcription Factors/metabolism; Green Fluorescent Proteins/metabolism; Humans; Image Processing, Computer-Assisted; Immunoprecipitation; Inhibin-beta Subunits/metabolism; Ligands; Male; Microscopy, Confocal; Plasmids/metabolism; Promoter Regions, Genetic; Prostatic Neoplasms/pathology; Protein Binding; RNA/chemistry; Receptors, Androgen/genetics; Receptors, Androgen/metabolism; Repressor Proteins/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Smad2 Protein/metabolism; Smad4 Protein/metabolism; Transcriptional Activation; Transfection; Two-Hybrid System Techniques
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:FOXH1	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P10275	F		Seeded From UniProt	complete
HUMAN:FOXH1	located_in	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:ANDR	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O75593	F		Seeded From UniProt	complete
HUMAN:ANDR	enables	GO:0001085: RNA polymerase II transcription factor binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O75593	F		Seeded From UniProt	complete
HUMAN:FOXH1	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:FOXH1	involved_in	GO:0033147: negative regulation of intracellular estrogen receptor signaling pathway	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:FOXH1	enables	GO:0050681: androgen receptor binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P10275	F		Seeded From UniProt	complete
HUMAN:FOXH1	involved_in	GO:0060766: negative regulation of androgen receptor signaling pathway	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:FOXH1	enables	GO:0070410: co-SMAD binding	ECO:0000315: mutant phenotype evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:FOXH1	enables	GO:0070412: R-SMAD binding	ECO:0000315: mutant phenotype evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:FOXH1	involved_in	GO:0043433: negative regulation of DNA-binding transcription factor activity	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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