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

Mol Cancer Res. 2007 Apr;5(4):383-91. doi: 10.1158/1541-7786.MCR-06-0226.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Prostate-Specific Antigen / metabolism*
  • Prostatic Neoplasms / metabolism*
  • Receptors, Androgen / metabolism
  • Transfection


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