The synovial sarcoma-associated SS18-SSX2 fusion protein induces epigenetic gene (De)regulation
The synovial sarcoma-associated SS18-SSX2 fusion protein induces epigenetic gene (De)regulation
复制标题
DOI：
10.1158/0008-5472.can-05-3726
复制
发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
van Kessel, Ad Geurts
中科院分区：
文献类型：
--
作者：
de Bruijn, Diederik R. H.;Allander, Susanne V.;van Kessel, Ad Geurts
SS 18和SSX基因的融合是人类滑膜肉瘤的标志。SS 18和SSX基因编码表现出相反的转录活性的核蛋白。SS 18蛋白作为转录辅激活因子发挥作用，并与SWI/SNF复合物相关，而SSX蛋白作为转录辅抑制因子发挥作用，并与polycomb复合物相关。参与这些相反转录活性的结构域保留在SS 18-SSX融合蛋白中。在这里，我们开始使用基于互补DNA微阵列的分析来确定条件SS 18-SSX 2融合蛋白表达的直接转录结果。通过这样做，我们确定了几个SS 18-SSX 2反应基因簇，包括一组参与胆固醇合成的基因，这是恶性肿瘤的一般特征。此外，我们鉴定了一组已知在原发性滑膜肉瘤中特异性失调的SS 18-SSX 2应答基因，包括IGF 2和CD 44。此外，我们观察到EGR 1，JUNB和WNT信号在响应SS 18-SSX 2表达中的解偶联，表明SS 18部分的SWI/SNF相关共激活功能受损。最后，我们发现SS 18-SSX 2表达影响CD 44和IGF 2启动子中的组蛋白修饰以及IGF 2印迹控制区中的DNA甲基化水平。总之，我们得出结论，SSIS-SSX 2融合蛋白可能作为一个所谓的转录“激活-阻遏”，诱导下游靶基因通过表观遗传机制失调。我们的研究结果可能对滑膜肉瘤的发展和临床治疗都有意义。
Fusion of the SS18 and either one of the SSX genes is a hallmark of human synovial sarcoma. The SS18 and SSX genes encode nuclear proteins that exhibit opposite transcriptional activities. The SS18 protein functions as a transcriptional coactivator and is associated with the SWI/SNF complex, whereas the SSX proteins function as transcriptional corepressors and are associated with the polycomb complex. The domains involved in these opposite transcriptional activities are retained in the SS18-SSX fusion proteins. Here, we set out to determine the direct transcriptional consequences of conditional SS18-SSX2 fusion protein expression using complementary DNA microarray-based profiling. By doing so, we identified several clusters of SS18-SSX2-responsive genes, including a group of genes involved in cholesterol synthesis, which is a general characteristic of malignancy. In addition, we identified a group of SS18-SSX2-responsive genes known to be specifically deregulated in primary synovial sarcomas, including IGF2 and CD44. Furthermore, we observed an uncoupling of EGR1, JUNB, and WNT signaling in response to SS18-SSX2 expression, suggesting that the SWI/SNF-associated coactivation functions of the SS18 moiety are impaired. Finally, we found that SS18-SSX2 expression affects histone modifications in the CD44 and IGF2 promoters and DNA methylation levels in the IGF2 imprinting control region. Together, we conclude that the SSIS-SSX2 fusion protein may act as a so-called transcriptional "activator-repressor," which induces downstream target gene deregulation through epigenetic mechanisms. Our results may have implications for both the development and clinical management of synovial sarcomas.