滑膜肉瘤中 SS18-SSX 致癌融合导致 mSWI/SNF（BAF）复合物的可逆破坏。
Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma.
机构信息
Program in Cancer Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
出版信息
Cell. 2013 Mar 28;153(1):71-85. doi: 10.1016/j.cell.2013.02.036.
Recent exon sequencing studies have revealed that over 20% of human tumors have mutations in subunits of mSWI/SNF (BAF) complexes. To investigate the underlying mechanism, we studied human synovial sarcoma (SS), in which transformation results from the translocation of exactly 78 amino acids of SSX to the SS18 subunit of BAF complexes. We demonstrate that the SS18-SSX fusion protein competes for assembly with wild-type SS18, forming an altered complex lacking the tumor suppressor BAF47 (hSNF5). The altered complex binds the Sox2 locus and reverses polycomb-mediated repression, resulting in Sox2 activation. Sox2 is uniformly expressed in SS tumors and is essential for proliferation. Increasing the concentration of wild-type SS18 leads to reassembly of wild-type complexes retargeted away from the Sox2 locus, polycomb-mediated repression of Sox2, and cessation of proliferation. This mechanism of transformation depends on only two amino acids of SSX, providing a potential foundation for therapeutic intervention.
最近的外显子测序研究表明，超过 20%的人类肿瘤存在 mSWI/SNF（BAF）复合物亚基的突变。为了研究其潜在机制，我们研究了人类滑膜肉瘤（SS），其转化是由 SSX 的 78 个氨基酸与 BAF 复合物的 SS18 亚基的易位引起的。我们证明，SS18-SSX 融合蛋白与野生型 SS18 竞争组装，形成缺乏肿瘤抑制因子 BAF47（hSNF5）的改变的复合物。改变的复合物结合 Sox2 基因座并逆转多梳介导的抑制，导致 Sox2 的激活。Sox2 在 SS 肿瘤中均匀表达，对于增殖是必需的。增加野生型 SS18 的浓度会导致重新组装针对 Sox2 基因座的野生型复合物，多梳介导的 Sox2 抑制以及增殖停止。这种转化机制仅依赖于 SSX 的两个氨基酸，为治疗干预提供了潜在的基础。
Zotero 插件