通过SS18-SSX在突肉瘤中的瘤性融合对mSWI/SNF (BAF) 复合物的可逆性破坏
Cigall Kadoch1, Gerald R Crabtree
1Program in Cancer Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell
|April 2, 2013
概括
在人类癌症中,SWI/SNF (BAF) 综合体的突变很常见. 在突肉瘤中,SS18-SSX融合蛋白破坏BAF复合体,激活Sox2基因并驱动瘤生长.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 超过20%的人类瘤在SWI/SNF (BAF) 复合体中存在突变.
- 突肉瘤 (SS) 的特征是涉及SS18和SSX基因的特定转位.
研究的目的:
- 阐明SS18-SSX融合蛋白驱动突肉瘤的分子机制.
- 研究BAF复合体和Sox2在SS病变发生中的作用.
主要方法:
- 研究了人类突肉瘤 (SS) 细胞模型.
- 分析了BAF复合体的组装及其与Sox2位置的相互作用.
- 评估了SS18-SSX对多介导抑制和Sox2激活的影响.
主要成果:
- SS18-SSX融合蛋白形成了一个异常的BAF复合体,缺少BAF47 (hSNF5).
- 这种改变的复合体准Sox2位点,逆转抑制并导致Sox2激活,这对SS扩散至关重要.
- 恢复野生类型的SS18水平重新组装了功能BAF复合体,抑制了Sox2,并阻止了扩散.
结论:
- SS18-SSX融合蛋白劫持BAF复合体以激活Sox2,这是突肉瘤的关键驱动因素.
- 这种致癌机制依赖于最小的SSX序列,这表明了有针对性的治疗方法.
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