Barco Roy, Garcia Christina B, Eid Josiane E
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
PLoS One. 2009;4(4):e5060. doi: 10.1371/journal.pone.0005060. Epub 2009 Apr 1.
This study demonstrates deregulation of polycomb activity by the synovial sarcoma-associated SYT-SSX2 oncogene, also known as SS18-SSX2. Synovial sarcoma is a soft tissue cancer associated with a recurrent t(X:18) translocation event that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. The role of the translocation products in this disease is poorly understood. We present evidence that the SYT-SSX2 fusion protein interacts with the polycomb repressive complex and modulates its gene silencing activity. SYT-SSX2 causes destabilization of the polycomb subunit Bmi1, resulting in impairment of polycomb-associated histone H2A ubiquitination and reactivation of polycomb target genes. Silencing by polycomb complexes plays a vital role in numerous physiological processes. In recent years, numerous reports have implicated gain of polycomb silencing function in several cancers. This study provides evidence that, in the appropriate context, expression of the SYT-SSX2 oncogene leads to loss of polycomb function. It challenges the notion that cancer is solely associated with an increase in polycomb function and suggests that any imbalance in polycomb activity could drive the cell toward oncogenesis. These findings provide a mechanism by which the SYT-SSX2 chimera may contribute to synovial sarcoma pathogenesis.
本研究证明滑膜肉瘤相关的SYT-SSX2致癌基因（也称为SS18-SSX2）对多梳蛋白活性的调控异常。滑膜肉瘤是一种软组织癌，与复发性t(X;18)易位事件相关，该事件产生两种融合蛋白之一，即SYT-SSX1或SYT-SSX2。人们对这种易位产物在该疾病中的作用了解甚少。我们提供的证据表明，SYT-SSX2融合蛋白与多梳蛋白抑制复合物相互作用并调节其基因沉默活性。SYT-SSX2导致多梳蛋白亚基Bmi1的稳定性下降，从而导致多梳蛋白相关的组蛋白H2A泛素化受损以及多梳蛋白靶基因的重新激活。多梳蛋白复合物介导的基因沉默在众多生理过程中起着至关重要的作用。近年来，大量报道表明多梳蛋白沉默功能的增强与多种癌症有关。本研究提供的证据表明，在适当的情况下，SYT-SSX2致癌基因的表达会导致多梳蛋白功能丧失。这对癌症仅与多梳蛋白功能增加相关的观点提出了挑战，并表明多梳蛋白活性的任何失衡都可能促使细胞发生肿瘤。这些发现提供了一种机制，通过该机制SYT-SSX2嵌合体可能促成滑膜肉瘤的发病机制。
