Residual Complexes Containing SMARCA2 (BRM) Underlie the Oncogenic Drive of SMARCA4 (BRG1) Mutation
Residual Complexes Containing SMARCA2 (BRM) Underlie the Oncogenic Drive of SMARCA4 (BRG1) Mutation
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DOI：
10.1128/mcb.01372-13
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发表时间：
2014-03-01
影响因子：
5.3
通讯作者：
Roberts, Charles W. M.
中科院分区：
文献类型：
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作者：
Wilson, Boris G.;Helming, Katherine C.;Roberts, Charles W. M.
总的来说，编码 SWI/SNF (BAF) 染色质重塑复合体亚基的基因在 20% 的人类癌症中发生突变，其中 SMARCA4 (BRG1) 亚基是最常见的突变之一。 SWI/SNF 复合物通过两个相互排斥的催化亚基 SMARCA4 和 SMARCA2 (BRM) 的活性来调节染色质重塑。在这里，我们发现含有 SMARCA2 的残留 SWI/SNF 复合物是 SMARCA4 突变癌症的致癌活性的基础。我们证明了 SMARCA4 突变细胞系中存在残留的 SWI/SNF 复合物，并在细胞增殖中发挥重要作用。此外，利用 165 个癌细胞系的功能丧失筛选数据，我们将 SMARCA2 确定为 SMARCA4 突变癌细胞系中的必需基因。从机制上讲，我们揭示了 Smarca4 失活导致非必需 SMARCA2 亚基更多地掺入 SWI/SNF 复合物中。总的来说，这些结果揭示了 SMARCA2 在 SMARCA4 缺失引起的肿瘤发生中的作用，并确定 ATP 酶和含有溴结构域的 SMARCA2 作为这些癌症的潜在治疗靶点。
Collectively, genes encoding subunits of the SWI/SNF (BAF) chromatin remodeling complex are mutated in 20% of all human cancers, with the SMARCA4 (BRG1) subunit being one of the most frequently mutated. The SWI/SNF complex modulates chromatin remodeling through the activity of two mutually exclusive catalytic subunits, SMARCA4 and SMARCA2 (BRM). Here, we show that a SMARCA2-containing residual SWI/SNF complex underlies the oncogenic activity of SMARCA4 mutant cancers. We demonstrate that a residual SWI/SNF complex exists in SMARCA4 mutant cell lines and plays essential roles in cellular proliferation. Further, using data from loss-of-function screening of 165 cancer cell lines, we identify SMARCA2 as an essential gene in SMARCA4 mutant cancer cell lines. Mechanistically, we reveal that Smarca4 inactivation leads to greater incorporation of the nonessential SMARCA2 subunit into the SWI/SNF complex. Collectively, these results reveal a role for SMARCA2 in oncogenesis caused by SMARCA4 loss and identify the ATPase and bromodomain-containing SMARCA2 as a potential therapeutic target in these cancers.