FOXA1 Promotes Tumor Progression in Prostate Cancer via the Insulin-Like Growth Factor Binding Protein 3 Pathway

Yusuke Imamura,Katsuhiro Uzawa,Naoki Nihei,Atsushi Mizokami,Takahito Suyama,Takeshi Ueda,Hideki Tanzawa,Tomohiko Ichikawa,Takumi Endo,Kojiro Yano,Takanobu Utsumi,Naohiko Seki,Takashi Imamoto,Miki Fuse,Koji Kawamura,Hiroyoshi Suzuki,Shinichi Sakamoto

doi:10.1371/journal.pone.0042456

Yusuke Imamura, Katsuhiro Uzawa + Show 15 more

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https://doi.org/10.1371/journal.pone.0042456

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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.

Highlights

Prostate cancer (PC), the most common cancer in men, is a second leading cause of cancer-related death in most of western countries and is becoming more common in Asian countries as well [1]
The present study investigated the role of Fork-head box protein A1 (FOXA1) in PC progression
We identified insulin-like growth factor binding protein 3 (IGFBP-3) as a novel target of FOXA1 for the regulation of cell proliferation in PC cells

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Prostate cancer (PC), the most common cancer in men, is a second leading cause of cancer-related death in most of western countries and is becoming more common in Asian countries as well [1]. The hormone androgen and the androgen receptor (AR) are essential for the normal growth, differentiation and maintenance of the prostate gland, and they play a critical role in the development of PC [2]. Treatment of advanced PC involves blocking the production of androgens or antagonizing AR and its target genes [1]. A recent study showed that a low level of intra-tumoral androgen during androgen ablation therapy continues to activate the AR, which leads to further progression of PC into metastasis [3]. Even at an advanced stage of PC, the regulation of AR activity is important for the treatment of PC

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