Androgen-dependent gene expression of prostate-specific antigen is enhanced synergistically by hypoxia in human prostate cancer cells.

Abstract

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.

• Authors: Kou Horii, Yasutomo Suzuki, Yukihiro Kondo, Masao Akimoto, Taiji Nishimura, Yukako Yamabe, Motoharu Sakaue, Toshihiro Sano, Takayuki Kitagawa, Seiichiro Himeno, Nobumasa Imura, Shuntaro Hara
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 5 Issue 4 Pg. 383-91 (Apr 2007) ISSN: 1541-7786 [Print] United States
• PMID: 17426252 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AR protein, human
• Androgens
• Hypoxia-Inducible Factor 1, alpha Subunit
• Receptors, Androgen
• Prostate-Specific Antigen

Topics

• Androgens (pharmacology)
• Animals
• Base Sequence
• COS Cells
• Cell Hypoxia
• Cell Line, Tumor
• Chlorocebus aethiops
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Molecular Sequence Data
• Promoter Regions, Genetic
• Prostate-Specific Antigen (genetics, metabolism)
• Prostatic Neoplasms (metabolism)
• Receptors, Androgen (metabolism)
• Transfection