SOX9 Is Expressed in Normal Prostate Basal Cells and Regulates Androgen Receptor Expression in Prostate Cancer Cells

Abstract

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 3B inhibitor (SB415286), and SOX9 was reduced when B-catenin was downregulated by small interfering RNA (siRNA), indicating that SOX9 expression in prostate cancer is regulated by Wnt/Bcatenin 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. [Cancer Res 2007;67(2):528-36]

SOXs in human prostate cancer: implication as progression and prognosis factors

“…In 2004, Drivdahl et al [23] found that the elevated expression of SOX9 in PCa cell lines resulted in a decreased rate of cellular proliferation, cell cycle arrest in G0/G1, and increased sensitivity to apoptosis. In 2007 and 2008, Wang et al [7,8] also demonstrated that SOX9 was expressed in PCa cells and was increased in relapsed hormonerefractory PCa. In 2010, Thomsen et al [12] identified SOX9 as part of a developmental pathway that is reactivated in prostate neoplasia where it promotes tumor cell proliferation.…”

“…Their potential roles have also been found in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. Of our interests, Wang et al [7,8] found that SOX9 is expressed in primary PCa in vivo, at a higher frequency in recurrent PCa and in PCa cell lines. They also demonstrated that the suppression of SOX9 by siRNA in PCa cells may reduce endogenous androgen receptor (AR) protein levels and cell growth, which suggested that SOX9 may contribute to androgen receptor regulation and decreased cellular proliferation of PCa.…”

SOX9 Regulates Low Density Lipoprotein Receptor-related Protein 6 (LRP6) and T-cell Factor 4 (TCF4) Expression and Wnt/β-catenin Activation in Breast Cancer

“…The siRNA transfection and retrovirus-mediated shRNA transduction were described (28,30). Lentiviruses expressing SOX9-specific or luciferase shRNA were generated by transfecting 293T cells with hairpin-pLKO.1 plasmids, together with packaging plasmids.…”

SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis

“…Kip1 in prostate cancer cells (Wang et al, 2007), indicating that SOX9 positively regulates cell-cycle progression though inhibiting p27…”