Modulation of androgen receptor transactivation by FoxH1. A newly identified androgen receptor corepressor.
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.
Chen
Guangchun
G
Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Nomura
Masatoshi
M
Morinaga
Hidetaka
H
Matsubara
Eri
E
Okabe
Taijiro
T
Goto
Kiminobu
K
Yanase
Toshihiko
T
Zheng
Hong
H
Lu
Jian
J
Nawata
Hajime
H
D028341:Activins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D047468:Immunoprecipitation; D028322:Inhibin-beta Subunits / Q000378:metabolism; D008024:Ligands; D008297:Male; D018613:Microscopy, Confocal; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000473:pathology; D011485:Protein Binding; D012313:RNA / Q000737:chemistry; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques
C510350:FOXH1 protein, human; D051858:Forkhead Transcription Factors; C491117:Foxh1 protein, mouse; D008024:Ligands; D011944:Receptors, Androgen; D012097:Repressor Proteins; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; C422405:activin A; D013196:Dihydrotestosterone; D028341:Activins; D049452:Green Fluorescent Proteins; D012313:RNA; D028322:Inhibin-beta Subunits