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

## TL;DR

This study shows how androgen signaling and vitamin D3 interact to regulate HOXC9, a gene that inhibits prostate cancer growth.

## Contribution

The study reveals a novel regulatory mechanism where HOXC9 is repressed by androgen signaling and activated by vitamin D3.

## Key findings

- HOXC9 is a common target gene regulated oppositely by androgen and vitamin D3.
- Androgen receptor preferentially suppresses HOXC9 through stronger binding and DNA methylation.
- Forced HOXC9 expression inhibits androgen-dependent prostate cancer proliferation.

## Abstract

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.