SOX9 is a member of the SOX [Sry-related high-mobility group (HMG) box] family of HMG
DNA-binding domain
transcription factors and is required for the development and differentiation of multiple cell lineages. This report shows that basal epithelial cells express SOX9 in normal prostate, with no detectable expression in
luminal epithelial cells. In contrast, SOX9 is expressed in primary
prostate cancers in vivo, at a higher frequency in recurrent
prostate cancer and in
prostate cancer cell lines (LNCaP, CWR22, PC3, and DU145). SOX9 message and
protein levels in
prostate cancer cells were increased by treatment with
glycogen synthase kinase 3beta inhibitor (
SB415286), and SOX9 was reduced when
beta-catenin was down-regulated by
small interfering RNA (
siRNA), indicating that SOX9 expression in
prostate cancer is regulated by Wnt/
beta-catenin signaling. SOX9 bound specifically to
androgen receptor (AR)
DNA-binding domain
glutathione S-transferase fusion
proteins, and this interaction was dependent on a short
peptide immediately COOH-terminal to the
DNA-binding domain (the C-terminal extension), which is required for interactions between
steroid hormone receptors and the architectural
HMG proteins. Exogenous SOX9 expressed at high nonphysiologic levels decreased AR expression and activity; however, at lower levels, SOX9 increased AR
protein expression. Significantly, down-regulation of SOX9 by
siRNA in
prostate cancer cells reduced endogenous AR
protein levels, and cell growth indicating that SOX9 contributes to AR regulation and decreased cellular proliferation. These results indicate that SOX9 in prostate basal cells supports the development and maintenance of the
luminal epithelium and that a subset of
prostate cancer cells may escape basal cell requirements through SOX9 expression.