The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Drosophila Imaginal Tissues.
The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Drosophila Imaginal Tissues.
复制标题
DOI：
10.1158/0008-5472.can-16-0963
复制
发表时间：
2017-02-15
期刊：
影响因子：
11.2
通讯作者：
Deng WM
中科院分区：
文献类型：
--
作者：
Xie G;Chen H;Jia D;Shu Z;Palmer WH;Huang YC;Zeng X;Hou SX;Jiao R;Deng WM
SWI/SNF染色质重塑复合体的组成部分是各种人类癌症中最常发生突变的基因之一，但只有SWI/SNF复合体的核心成员SMARCB1/hSNF5在恶性横纹肌样肿瘤（MRT）中发生突变。smarcb1 /hSNF5的功能与SWI/SNF复合体的其他成员有何不同尚不清楚。在这里，我们使用果蝇的想象上皮组织来证明Snr1，人类SMARCB1/hSNF5的保守同源物，通过维持正常的内体运输介导的信号级联来阻止肿瘤发生。Snr1的去除会导致影像上皮组织的肿瘤致瘤性过度生长，而SWI/SNF复合物的任何其他成员的去除都不会诱导类似的表型。与仅在细胞核中检测到的SWI/SNF复合物的其他组分不同，Snr1在细胞核和细胞质中都被观察到。多种信号通路的异常调控，包括Notch、JNK和JAK/STAT，是snr1耗损后肿瘤进展的原因。我们的研究结果表明，细胞质Snr1可能在果蝇想象组织中发挥肿瘤抑制作用，为理解SMARCB1/hSNF5在儿童早期抑制MRT中的关键作用提供了基础。
Components of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in various human cancers, yet only SMARCB1/hSNF5, a core member of the SWI/SNF complex, is mutated in malignant rhabdoid tumors (MRT). HowSMARCB1/hSNF5 functions differently from other members of the SWI/SNF complex remains unclear. Here, we use Drosophila imaginal epithelial tissues to demonstrate that Snr1, the conserved homolog of human SMARCB1/hSNF5, prevents tumorigenesis by maintaining normal endosomal trafficking-mediated signaling cascades. Removal of Snr1 resulted in neoplastic tumorigenic overgrowth in imaginal epithelial tissues, whereas depletion of any other members of the SWI/SNF complex did not induce similar phenotypes. Unlike other components of the SWI/SNF complex that were detected only in the nucleus, Snr1 was observed in both the nucleus and the cytoplasm. Aberrant regulation of multiple signaling pathways, including Notch, JNK, and JAK/STAT, was responsible for tumor progression upon snr1-depletion. Our results suggest that the cytoplasmic Snr1 may play a tumor suppressive role in Drosophila imaginal tissues, offering a foundation for understanding the pivotal role of SMARCB1/hSNF5 in suppressing MRT during early childhood.