title: FOXA1 promotes tumor progression in prostate cancer via the insulin-like growth factor binding protein 3 pathway.
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.
authors.affiliation: Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Imamura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Takumi
authors.initials: T
authors.lastname: Endo
authors.forename: Takanobu
authors.initials: T
authors.lastname: Utsumi
authors.forename: Miki
authors.initials: M
authors.lastname: Fuse
authors.forename: Takahito
authors.initials: T
authors.lastname: Suyama
authors.forename: Koji
authors.initials: K
authors.lastname: Kawamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Imamoto
authors.forename: Kojiro
authors.initials: K
authors.lastname: Yano
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Uzawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Nihei
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizokami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueda
authors.forename: Naohiko
authors.initials: N
authors.lastname: Seki
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanzawa
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ichikawa
mesh_terms: D000368:Aged; D002369:Castration; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: C410798:AR protein, human; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D011944:Receptors, Androgen; D013002:Somatomedins