We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
FOXA1 Promotes Tumor Progression in Prostate Cancer via the Insulin-Like Growth Factor Binding Protein 3 Pathway.
- Authors
Imamura, Yusuke; Sakamoto, Shinichi; Endo, Takumi; Utsumi, Takanobu; Fuse, Miki; Suyama, Takahito; Kawamura, Koji; Imamoto, Takashi; Yano, Kojiro; Uzawa, Katsuhiro; Nihei, Naoki; Suzuki, Hiroyoshi; Mizokami, Atsushi; Ueda, Takeshi; Seki, Naohiko; Tanzawa, Hideki; Ichikawa, Tomohiko; Agoulnik, Irina
- Abstract
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.
- Subjects
ANDROGEN receptors; PROTEINS; PROSTATE cancer; CELL proliferation; INSULIN-like growth factor-binding proteins; PHOSPHORYLATION
- Publication
PLoS ONE, 2012, Vol 7, Issue 8, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0042456