Molecular Pathology Graduate Program, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
PLoS One. 2012;7(4):e35570. doi: 10.1371/journal.pone.0035570. Epub 2012 Apr 19.
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.
前列腺癌受涉及癌症发生和发展的基因的表观遗传修饰的影响。前列腺干细胞抗原（PSCA）的表达增加与恶性人类前列腺癌的发展相关，而小鼠模型的研究表明 PSCA 水平的降低会促进前列腺癌转移。这些研究表明 PSCA 具有上下文相关的功能，并且在肿瘤进展过程中可能会受到差异调节。在本研究中，我们确定多功能转录因子 Yin Yang 1（YY1）是前列腺上皮细胞系中 PSCA 表达的调节剂。在前列腺上皮内瘤变（PIN）和晚期疾病中观察到 YY1 水平增加。我们表明雄激素介导的前列腺上皮细胞系中 PSCA 的上调依赖于 YY1。我们在 PSCA 启动子内鉴定了两个直接的 YY1 结合位点，并表明上游位点抑制，而下游位点靠近雄激素反应元件，刺激 PSCA 启动子活性。因此，前列腺癌中 PSCA 表达水平的变化至少部分可能受 YY1 的细胞水平影响。我们的结果还表明 YY1 在前列腺癌中具有多种作用，通过调节 PSCA 等基因可能促进疾病进展。
