Abstract
The expression of the WWOX tumor suppressor gene is lost or reduced in a large fraction of various cancers, including prostate cancer. We previously reported that Wwox overexpression induced apoptosis and suppressed prostate cancer growth in vitro and in vivo. In this study, pathways through which Wwox contributes to control of prostate cancer cell growth have been investigated. We found that Wwox interacts with Ap2gamma and prevents it from entering the nucleus to bind the ERBB2 promoter region to activate transcription of ERBB2, a mediator of androgen receptor activity and prostate cancer cell growth at limiting androgen concentration. Ectopic expression of Wwox reduced ErbB2 protein expression in vitro and expression of Wwox protein inversely correlated with expression of ErbB2 protein in prostate cancer tissues. Furthermore, Wwox suppressed Ap2gamma/ErbB2-induced prostate cancer cell growth and suppressed prostate-specific antigen secretion through interaction with Ap2gamma and down-modulation of ErbB2, an effect that required functional androgen receptor.
Highlights
The tumor-suppressor gene, WWOX (WW domain containing oxidoreductase), spans one of the most active fragile sites, FRA16D, at chromosome 16q23.3-24.1, a region exhibiting loss of heterozygosity in breast, prostate, and other cancers [1,2,3]
We previously showed that Wwox expression is reduced or lost in prostate cancer – derived cells and tissues, in part due to hypermethylation in the WWOX regulatory region, and that overexpression of exogenous WWOX induced apoptosis in prostate cancer cells and suppressed prostate cancer growth in vitro and in vivo [6]
We explored the effect of Wwox restoration on Ap2g and ErbB2 signaling in LNCaP (AR positive) and DU145 (AR negative) prostate cancer – derived cells, which express low endogenous Wwox levels [6], and the relevance of Wwox-mediated effects to prostate cancer cell growth and androgen receptor (AR) signaling
Summary
The tumor-suppressor gene, WWOX (WW domain containing oxidoreductase), spans one of the most active fragile sites, FRA16D, at chromosome 16q23.3-24.1, a region exhibiting loss of heterozygosity in breast, prostate, and other cancers [1,2,3]. Ectopic expression of Ap2g, leading to increased expression of ErbB2 (Fig. 4B), resulted in increased LNCaP cell growth in an androgen-independent environment, which was completely suppressed by wild-type Wwox but not mutant WwoxY33R.
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