Androgen Regulation of the TMPRSS2 Gene and the Effect of a SNP in an Androgen Response Element
Androgen Regulation of the TMPRSS2 Gene and the Effect of a SNP in an Androgen Response Element
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DOI：
10.1210/me.2013-1098
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发表时间：
2013-12-01
影响因子：
--
通讯作者：
Claessens, Frank
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文献类型：
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作者：
Clinckemalie, Liesbeth;Spans, Lien;Claessens, Frank
超过 50% 的前列腺癌经历了基因组重组，将 TMPRSS2 的雄激素调节启动子与几个 ETS 癌基因的蛋白质编码部分并置。这些基因融合导致前列腺特异性和雄激素诱导的 ETS 表达，并与侵袭性病变、不良预后和早发性前列腺癌相关。在这项研究中，我们表明，当在细菌人工染色体载体中进行测试时，TMPRSS2 转录起始位点上游 13 kb 的增强子对于 TMPRSS2 基因的雄激素调节至关重要。在这个增强子中，我们确定了确切的雄激素受体结合序列。这个新发现的雄激素反应元件位于先驱因子 GATA2 的两个结合位点附近，这两个结合位点是通过 DNase I 足迹法识别的。雄激素反应元件和 GATA-2 结合位点均参与增强子活性。重要的是，该雄激素反应元件内的单核苷酸多态性（rs8134378）减少了雄激素受体的结合和反式激活。该 SNP 的存在可能会对 TMPRSS2 融合体的表达和/或形成水平产生影响，因为两者均已被证明受到雄激素的影响。
More than 50% of prostate cancers have undergone a genomic reorganization that juxtaposes the androgen-regulated promoter of TMPRSS2 and the protein coding parts of several ETS oncogenes. These gene fusions lead to prostate-specific and androgen-induced ETS expression and are associated with aggressive lesions, poor prognosis, and early-onset prostate cancer. In this study, we showed that an enhancer at 13 kb upstream of the TMPRSS2 transcription start site is crucial for the androgen regulation of the TMPRSS2 gene when tested in bacterial artificial chromosomal vectors. Within this enhancer, we identified the exact androgen receptor binding sequence. This newly identified androgen response element is situated next to two binding sites for the pioneer factor GATA2, which were identified by DNase I footprinting. Both the androgen response element and the GATA-2 binding sites are involved in the enhancer activity. Importantly, a single nucleotide polymorphism (rs8134378) within this androgen response element reduces binding and transactivation by the androgen receptor. The presence of this SNP might have implications on the expression and/or formation levels of TMPRSS2 fusions, because both have been shown to be influenced by androgens.