Human PIRH2 enhances androgen receptor signaling through inhibition of histone deacetylase 1 and is overexpressed in prostate cancer.
The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer.
Logan
Ian R
IR
University of Newcastle Upon Tyne, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH, United Kingdom.
Gaughan
Luke
L
McCracken
Stuart R C
SR
Sapountzi
Vasileia
V
Leung
Hing Y
HY
Robson
Craig N
CN
D049109:Cell Proliferation; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008297:Male; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
C410798:AR protein, human; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D011944:Receptors, Androgen; D012097:Repressor Proteins; D025801:Ubiquitin; C485369:RCHY1 protein, human; D044767:Ubiquitin-Protein Ligases; D017430:Prostate-Specific Antigen; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1