%0 Journal Article
%T FOXA1 Promotes Tumor Progression in Prostate Cancer via the Insulin-Like Growth Factor Binding Protein 3 Pathway
%A Yusuke Imamura
%A Shinichi Sakamoto
%A Takumi Endo
%A Takanobu Utsumi
%A Miki Fuse
%A Takahito Suyama
%A Koji Kawamura
%A Takashi Imamoto
%A Kojiro Yano
%A Katsuhiro Uzawa
%A Naoki Nihei
%A Hiroyoshi Suzuki
%A Atsushi Mizokami
%A Takeshi Ueda
%A Naohiko Seki
%A Hideki Tanzawa
%A Tomohiko Ichikawa
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0042456
%X Fork-head box protein A1 (FOXA1) is a ˇ°pioneer factorˇ± 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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0042456