Identification of a core member of the SWI/SNF complex, BAF155/SMARCC1, as a human tumor suppressor gene
Identification of a core member of the SWI/SNF complex, BAF155/SMARCC1, as a human tumor suppressor gene
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DOI：
10.4161/epi.6.12.18492
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发表时间：
2011-12-01
期刊：
影响因子：
3.7
通讯作者：
Weissman, Bernard E.
中科院分区：
文献类型：
--
作者：
DelBove, Jessica;Rosson, Gary;Weissman, Bernard E.
最近的研究证实，SWI/SNF染色质重塑复合体的两个核心成员BRG1和SNF5/INI1在人类和小鼠肿瘤中具有肿瘤抑制活性。虽然第三个核心成员BAF155已被多项研究证实在肿瘤发生中具有潜在作用，但仍缺乏直接证据证明其具有肿瘤抑制活性。因此，我们在大量的人类肿瘤细胞系中筛选出BAF155缺失。我们鉴定了两个细胞系，SNUC2B结肠癌和SKOV3卵巢癌，显示出蛋白表达完全丧失，同时保持了正常的mRNA表达水平。SKOV3细胞系具有杂合性4bp缺失，导致855AA截短蛋白，而SNUC2B细胞系BAF155表达缺失的原因似乎是转录后错误。然而，缺乏可检测到的BAF155表达并不影响对RB介导的细胞周期停滞的敏感性。在这两个癌细胞系中，BAF155的全长而不是截短形式的重新表达会导致以复制衰老为特征的集落形成能力降低，但不会导致细胞凋亡。总之，这些数据表明，BAF155表达的缺失代表了在人类癌症发展过程中SWI/SNF复合体活性失活的另一种机制。我们的结果进一步表明，富含Pro-谷氨酰胺结构域的C-末端在该蛋白的肿瘤抑制活性中起着关键作用。
Recent studies have established that two core members of the SWI/SNF chromatin remodeling complex, BRG1 and SNF5/INI1, possess tumor-suppressor activity in human and mouse cancers. While the third core member, BAF155, has been implicated by several studies as having a potential role in tumor development, direct evidence for its tumor suppressor activity has remained lacking. Therefore, we screened for BAF155 deficiency in a large number of human tumor cell lines. We identified two cell lines, the SNUC2B colon carcinoma and the SKOV3 ovarian carcinoma, displaying a complete loss of protein expression while maintaining normal levels of mRNA expression. The SKOV3 cell line possesses a heterozygous 4 bp deletion that results in an 855AA truncated protein, while the cause of the loss of BAF155 expression in the SNUC2B cell line appears due to a post-transcriptional error. However, the lack of detectable BAF155 expression did not affect sensitivity to RB-mediated cell cycle arrest. Re-expression of full length but not a truncated form of BAF155 in the two cancer cell lines leads to reduced colony forming ability characterized by replicative senescence but not apoptosis. Collectively, these data suggest that loss of BAF155 expression represents another mechanism for inactivation of SWI/SNF complex activity in the development in human cancer. Our results further indicate that the c-terminus proline-glutamine rich domain plays a critical role in the tumor suppressor activity of this protein.