FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells.
Prostate cancer progression to the androgen-independent (AI) state involves acquisition of pathways that allow tumor growth under low-androgen conditions. We hypothesized that expression of molecular chaperones that modulate androgen binding to AR might be altered in prostate cancer and contribute to progression to the AI state. Here, we report that the Hsp90 cochaperone FKBP51 is upregulated in LAPC-4 AI tumors grown in castrated mice and describe a molecular mechanism by which FKBP51 regulates AR activity. Using recombinant proteins, we show that FKBP51 stimulates recruitment of the cochaperone p23 to the ATP-bound form of Hsp90, forming an FKBP51-Hsp90-p23 superchaperone complex. In cells, FKBP51 expression promotes superchaperone complex association with AR and increases the number of AR molecules that undergo androgen binding. FKBP51 stimulates androgen-dependent transcription and cell growth, and FKBP51 is part of a positive feedback loop that is regulated by AR and androgen. Finally, depleting FKBP51 levels by short hairpin RNA reduces the transcript levels of genes regulated by AR and androgen. Because the superchaperone complex plays a critical role in determining the ligand-binding competence and transcription function of AR, it provides an attractive target for inhibiting AR activity in prostate cancer cells.
Ni
Li
L
Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Yang
Chun-Song
CS
Gioeli
Daniel
D
Frierson
Henry
H
Toft
David O
DO
Paschal
Bryce M
BM
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D046912:Multiprotein Complexes; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D000099159:Tacrolimus Binding Protein 5
D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; D019746:Intramolecular Oxidoreductases; D046912:Multiprotein Complexes; D000071876:Prostaglandin-E Synthases; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C410798:AR protein, human