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Signaling and Regulation

Androgen-Dependent Gene Expression of Prostate-Specific Antigen Is Enhanced Synergistically by Hypoxia in Human Prostate Cancer Cells

¹ Department of Public Health, School of Pharmaceutical Sciences, Kitasato University; ² Department of Urology, Nippon Medical School; ³ Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan; ⁴ Department of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan; and ⁵ The Pharmaceutical Research Center, Iwate Medical School, Iwate, Japan

Requests for reprints: Shuntaro Hara, Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo 142-8555, Japan. Phone: 81-3-3784-8197; Fax: 81-3-3784-8245. E-mail: haras{at}pharm.showa-u.ac.jp

The androgen receptor (AR) is implicated in prostate cancer growth, progression, and angiogenesis. Hypoxia-inducible factor-1 (HIF-1), which transcriptionally regulates hypoxia-inducible angiogenic factors, is up-regulated in prostate cancers compared with adjacent normal tissues. HIF-1 may be involved in prostate cancer as well as the AR, but the involvement of HIF-1 in prostate cancer angiogenesis and progression has not been fully elucidated. In the present study, we found that in prostate cancer LNCaP cells dihydrotestosterone enhanced the expression of GLUT-1, one of the HIF-1 target genes, and also that hypoxia enhanced the expression of prostate-specific antigen (PSA) that is one of the AR target genes and is involved in tumor invasion. Small interfering RNA that specifically inhibits HIF-1 reduced the expression levels of PSA as well as GLUT-1. Reporter gene analysis showed that dihydrotestosterone activated the HIF-1–mediated gene expression and hypoxia enhanced the AR-induced promoter activity of human PSA gene. Deletion and site-directed mutation of the 5'-flanking region of human PSA gene revealed that the sequence ACGTG between –3951 and –3947 was essential in the response to hypoxia. Furthermore, chromatin immunoprecipitation assay indicated that HIF-1 interacts with the AR on the human PSA gene promoter. These results indicated that in prostate cancers, HIF-1 might cooperate with the AR to activate the expression of several genes related to tumor angiogenesis, invasion, and progression. (Mol Cancer Res 2007;5(4):383–91)