Androgen Signaling Represses Homeobox C9, an Inhibitor of Androgen Receptor, in Prostate Cancer Cells

Because prostate cancer proliferates in an androgen-dependent manner, various inhibitors of androgen production and antagonists of the androgen receptor (AR) are used as therapeutic agents. However, the emergence of castration-resistant prostate cancer has prompted the development of additional treatment strategies. In this study, we focused on the antiprostate cancer effects of vitamin D3 and examined novel antiproliferative effects through the crosstalk with androgen signaling. In human prostate cancer LNCaP cells, homeobox C9 (HOXC9) was identified as a common regulated target gene by dihydroxytestosterone and 1α,25-dihydroxyvitamin D3, but in opposite directions. Ligand-stimulated AR and vitamin D receptor competitively shared binding sites in the HOXC9 regulatory region, but dihydroxytestosterone stimulation preferentially suppressed HOXC9 expression due to the stronger binding properties of AR and the induction of DNA methylation. Forced expression of HOXC9 inhibited androgen signaling to eliminate the androgen-dependent proliferation by associating with the AR transcription complex, in part due to interference with AR binding to some of its targets in LNCaP cells. In summary, this study provides evidence for the involvement of HOXC9 in antiproliferative effects through a regulatory mechanism mediated by a crosstalk between vitamin D receptor and AR.