Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex.
Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex.
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DOI：
10.1158/0008-5472.can-09-0733
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发表时间：
2009-10-15
期刊：
影响因子：
11.2
通讯作者：
Roberts CW
中科院分区：
文献类型：
--
作者：
Wang X;Sansam CG;Thom CS;Metzger D;Evans JA;Nguyen PT;Roberts CW
染色质的改变在致癌转化中起着重要的作用，尽管其潜在的机制通常知之甚少。SWI/SNF复合体通过利用ATP水解的能量重塑染色质，从而调节靶基因的转录，从而参与表观遗传调控。SNF5是SWI/SNF复合体的核心亚单位，是一种有效的肿瘤抑制因子，在几种类型的人类癌症中特异性失活。然而，SNF5突变导致癌症的机制以及SNF5在SWI/SNF复合体中的作用在很大程度上仍不清楚。有人假设，在没有SNF5的情况下，肿瘤发生是由于SWI/SNF复合体功能丧失所致。然而，我们在这里展示了在原代细胞中对Snf5和ATPase亚单位BRG1失活的明显影响。此外，使用人类细胞系和小鼠模型，我们表明，在没有SNF5的情况下，癌症的形成不是由于SWI/SNF失活，而是肿瘤的形成依赖于BRG1的持续存在。总而言之，我们的结果表明，在没有SNF5的情况下，癌症的形成取决于残留的含有BRG1的SWI/SNF复合体的活性。这些发现表明，就像癌基因成瘾的概念一样，靶向抑制SWI/SNF ATPase活性可能是治疗侵袭性SNF5缺陷人类肿瘤的有效方法。
Alterations in chromatin play an important role in oncogenic transformation although the underlying mechanisms are often poorly understood. The SWI/SNF complex contributes to epigenetic regulation by utilizing the energy of ATP hydrolysis to remodel chromatin and thus regulate transcription of target genes. SNF5, a core subunit of the SWI/SNF complex, is a potent tumor suppressor that is specifically inactivated in several types of human cancer. However, the mechanism by which SNF5 mutation leads to cancer and the role of SNF5 within the SWI/SNF complex remains largely unknown. It has been hypothesized that oncogenesis in the absence of SNF5 occurs due to a loss of function of the SWI/SNF complex. Here we show, however, distinct effects for inactivation of Snf5 and the ATPase subunit Brg1 in primary cells. Further, using both human cell lines and mouse models, we show that cancer formation in the absence of SNF5 does not result from SWI/SNF inactivation but rather that oncogenesis is dependent upon continued presence of BRG1. Collectively, our results demonstrate that cancer formation in the absence of SNF5 is dependent upon the activity of the residual BRG1-containing SWI/SNF complex. These findings suggest that, much like the concept of oncogene addiction, targeted inhibition of SWI/SNF ATPase activity may be an effective therapeutic approach for aggressive SNF5 deficient human tumors.