Hypoxia enhances transcriptional activity of androgen receptor through hypoxia-inducible factor-1α in a low androgen environment.
The androgen receptor (AR) acts as a ligand-dependent transcriptional factor controlling development or progression of prostate cancer. Androgen ablation by castration is an effective therapy for prostate cancer, whereas eventually most of the tumors convert from a hormone-sensitive to a hormone-refractory disease state and grow even in a low androgen environment (e.g., 0.1nM 5α-dihydrotestosterone (DHT)) like the castration-resistant stage. Androgen ablation results in hypoxia, and solid tumors possess hypoxic environments. Hypoxia-inducible factor (HIF)-1, which is composed of HIF-1α and HIF-1β/ARNT subunits, functions as a master transcription factor for hypoxia-inducible genes. Here, we report that hypoxia enhances AR transactivation in the presence of 0.05 and 0.1nM DHT in LNCaP prostate cancer cells. siRNA-mediated knockdown of HIF-1α inhibited hypoxia-enhanced AR transactivation. Its inhibition by HIF-1α siRNA was canceled by expression of a siRNA-resistant form of HIF-1α. HIF-1α siRNA repressed hypoxia-stimulated expression of the androgen-responsive NKX3.1 gene in the presence of 0.1nM DHT, but not in the absence of DHT. In hypoxia, HIF-1α siRNA-repressed AR transactivation was restored in mutants in which HIF-1α lacked DNA-binding activity. Furthermore, a dominant negative form of HIF-1α canceled hypoxia-enhanced AR transactivation, and HIF-1β/ARNT siRNAs had no influence on hypoxia-enhanced AR transactivation. These results indicate that hypoxia leads to HIF-1α-mediated AR transactivation independent of HIF-1 activity and that HIF-1β/ARNT is not necessarily required for the transactivation.
Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 5998531, Japan.
Takakazu
T
Mitani
Ryoichi
R
Yamaji
Yasuki
Y
Higashimura
Naoki
N
Harada
Yoshihisa
Y
Nakano
Hiroshi
H
Inui
D000728:Androgens / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D000728:Androgens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011944:Receptors, Androgen