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.
Written by:
Mitani T, Harada N, Nakano Y, Inui H, Yamaji R. Are you the author?
Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531.
Reference: J Biol Chem. 2012 Sep 28;287(40):33594-606.
doi: 10.1074/jbc.M112.388298
PubMed Abstract
PMID: 22865883
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