Abstract
Prostate cancer is influenced by epigenetic modification of genes involved in cancer development and progression. Increased expression of Prostate Stem Cell Antigen (PSCA) is correlated with development of malignant human prostate cancer, while studies in mouse models suggest that decreased PSCA levels promote prostate cancer metastasis. These studies suggest that PSCA has context-dependent functions, and could be differentially regulated during tumor progression. In the present study, we identified the multi-functional transcription factor Yin Yang 1 (YY1) as a modulator of PSCA expression in prostate epithelial cell lines. Increased YY1 levels are observed in prostatic intraepithelial neoplasia (PIN) and advanced disease. We show that androgen-mediated up-regulation of PSCA in prostate epithelial cell lines is dependent on YY1. We identified two direct YY1 binding sites within the PSCA promoter, and showed that the upstream site inhibited, while the downstream site, proximal to the androgen-responsive element, stimulated PSCA promoter activity. Thus, changes in PSCA expression levels in prostate cancer may at least partly be affected by cellular levels of YY1. Our results also suggest multiple roles for YY1 in prostate cancer which may contribute to disease progression by modulation of genes such as PSCA.
Highlights
Prostate cancer is a heterogeneous disease arising from genetic events such as Pten deletion which result in tumor initiation [1,2,3]
Previous work showed that Prostate Stem Cell Antigen (PSCA) expression is reduced after castration [29,34], and increased when androgen is provided exogenously, likely due to binding of androgen to an androgenresponsive element (ARE) within the PSCA promoter [13]
We demonstrated that the multifunctional transcriptional factor Yin Yang 1 (YY1) binds directly to the PSCA promoter and regulates PSCA expression in androgen-dependent and independent cell lines
Summary
Prostate cancer is a heterogeneous disease arising from genetic events such as Pten deletion which result in tumor initiation [1,2,3]. PSCA over-expression is reported in a subset of prostate cancers at all stages from PIN to metastatic disease [8]. This protein has been considered as a target for therapy [8,9] and imaging [10] of prostate cancer, its function is still unknown. In addition our studies in a murine prostate cancer model showed that loss of PSCA promotes tumor metastasis [12]. Together, these data suggest that changes in PSCA expression levels may alter tumor development and progression
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