title: Coordinated action of hypoxia-inducible factor-1α and β-catenin in androgen receptor signaling.
abstract: The androgen receptor (AR) acts as a ligand-dependent transcriptional factor and plays a critical role in the development and progression of androgen-dependent and castration-resistant prostate cancer. Castration results in hypoxia in prostate cancer cells, and hypoxia enhances transcriptional activity of AR through hypoxia-inducible factor (HIF)-1α at low serum androgen levels mimicking the castration-resistant stage. However, HIF-1α is necessary but not sufficient for hypoxia-activated AR transactivation, and the molecular mechanism that regulates AR function in castration-resistant prostate cancer remains unclear. Here, we report that β-catenin is required for HIF-1α-mediated AR transactivation in hypoxic LNCaP prostate cancer cells under low androgen conditions. HIF-1α and β-catenin coordinately enhanced AR N-terminal and C-terminal interaction. β-Catenin accumulated in the nucleus in the HIF-1α protein-positive cells of LNCaP xenografts in castrated mice. In LNCaP cells, when HIF-1α was knocked down or was exogenously expressed in the cytoplasm, hypoxia-induced nuclear localization of β-catenin was inhibited. β-Catenin formed a complex with HIF-1α both in the nucleus and in the cytoplasm. Hypoxia increased the amount of a complex composed of AR and β-catenin, and knockdown of HIF-1α attenuated the recruitment of AR and β-catenin to the androgen response elements (AREs) of androgen-responsive genes. Furthermore, together with β-catenin, HIF-1α bound to the AREs in the presence of androgen. These results demonstrate that (i) HIF-1α and β-catenin coordinately enhance AR transactivation by accelerating N-terminal and C-terminal interaction; (ii) HIF-1α promotes nuclear translocation of β-catenin in hypoxia; and (iii) AR, HIF-1α, and β-catenin form a ternary complex on AREs.
authors.affiliation: Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan.
authors.forename: Takakazu
authors.initials: T
authors.lastname: Mitani
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inui
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Yamaji
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction; D015533:Transcriptional Activation; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011944:Receptors, Androgen; D051176:beta Catenin