by Yusuke Imamura, Shinichi Sakamoto, Takumi Endo, Takanobu Utsumi, Miki Fuse, Takahito Suyama, Koji Kawamura, Takashi Imamoto, Kojiro Yano, Katsuhiro Uzawa, Naoki Nihei, Hiroyoshi Suzuki, Atsushi Mizokami, Takeshi Ueda, Naohiko Seki, Hideki Tanzawa, Tomohiko Ichikawa
Fork-head box protein A1 (FOXA1) is a “pioneer factor” that is known to bind to the androgen receptor (AR) and regulate the transcription of AR-specific genes. However, the precise role of FOXA1 in prostate cancer (PC) remains unknown. In this study, we report that FOXA1 plays a critical role in PC cell proliferation. The expression of FOXA1 was higher in PC than in normal prostate tissues (P?=?0.0002), and, using immunohistochemical analysis, we found that FOXA1 was localized in the nucleus. FOXA1 expression levels were significantly correlated with both PSA and Gleason scores (P?=?0.016 and P?=?0.031, respectively). Moreover, FOXA1 up-regulation was a significant factor in PSA failure (P?=?0.011). Depletion of FOXA1 in a prostate cancer cell line (LNCaP) using small interfering RNA (siRNA) significantly inhibited AR activity, led to cell-growth suppression, and induced G0/G1 arrest. The anti-proliferative effect of FOXA1 siRNA was mediated through insulin-like growth factor binding protein 3 (IGFBP-3). An increase in IGFBP-3, mediated by depletion of FOXA1, inhibited phosphorylation of MAPK and Akt, and increased expression of the cell cycle regulators p21 and p27. We also found that the anti-proliferative effect of FOXA1 depletion was significantly reversed by simultaneous siRNA depletion of IGFBP-3. These findings provide direct physiological and molecular evidence for a role of FOXA1 in controlling cell proliferation through the regulation of IGFBP-3 expression in PC.