Androgen-dependent gene expression of prostate-specific antigen is enhanced synergistically by hypoxia in human prostate cancer cells.
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.
Horii
Kou
K
Department of Public Health, School of Pharmaceutical Sciences, Kitasato University, Japan.
Suzuki
Yasutomo
Y
Kondo
Yukihiro
Y
Akimoto
Masao
M
Nishimura
Taiji
T
Yamabe
Yukako
Y
Sakaue
Motoharu
M
Sano
Toshihiro
T
Kitagawa
Takayuki
T
Himeno
Seiichiro
S
Imura
Nobumasa
N
Hara
Shuntaro
S
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D014162:Transfection
C410798:AR protein, human; D000728:Androgens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen