Hypoxia enhances transcriptional activity of androgen receptor through hypoxia-inducible factor-1α in a low androgen environment.

Abstract

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.

• Authors: Takakazu Mitani, Ryoichi Yamaji, Yasuki Higashimura, Naoki Harada, Yoshihisa Nakano, Hiroshi Inui
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 123 Issue 1-2 Pg. 58-64 (Jan 2011) ISSN: 1879-1220 [Electronic] England
• PMID: 21056661 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Androgens
• Hypoxia-Inducible Factor 1, alpha Subunit
• Receptors, Androgen

Topics

• Androgens (metabolism)
• Cell Hypoxia
• Cell Line, Tumor
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Male
• Microscopy, Fluorescence
• Prostatic Neoplasms (genetics, pathology)
• Receptors, Androgen (genetics, metabolism)
• Transcriptional Activation