Inhibition of MYC by the SMARCB1 tumor suppressor
Inhibition of MYC by the SMARCB1 tumor suppressor
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DOI：
10.1038/s41467-019-10022-5
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发表时间：
2019-05-01
影响因子：
16.6
通讯作者：
Tansey, William P.
中科院分区：
文献类型：
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作者：
Weissmiller, April M.;Wang, Jing;Tansey, William P.
SMARCB 1编码SWI/SNF染色质重塑物的SNF 5亚基。SNF 5还与癌蛋白转录因子MYC相互作用，并被认为刺激MYC活性。然而，SNF 5是MYC的共激活因子的概念与其作为肿瘤抑制因子的作用以及SNF 5的缺失导致MYC靶基因激活的观察结果不一致。在这里，我们使用生物化学和全基因组方法重新检查MYC和SNF 5之间的关系。我们发现SNF 5抑制MYC的DNA结合能力，并阻碍细胞中MYC对靶基因的识别。我们进一步表明，通过SNF 5的MYC调控与其在染色质重塑中的作用是分离的，并且SNF 5重新引入SMARCB 1-null细胞模拟MYC抑制的主要转录效应。这些观察结果表明，SNF 5拮抗MYC，并提供了一种机制来解释SNF 5的丢失如何驱动恶性肿瘤。
SMARCB1 encodes the SNF5 subunit of the SWI/SNF chromatin remodeler. SNF5 also interacts with the oncoprotein transcription factor MYC and is proposed to stimulate MYC activity. The concept that SNF5 is a coactivator for MYC, however, is at odds with its role as a tumor-suppressor, and with observations that loss of SNF5 leads to activation of MYC target genes. Here, we reexamine the relationship between MYC and SNF5 using biochemical and genome-wide approaches. We show that SNF5 inhibits the DNA-binding ability of MYC and impedes target gene recognition by MYC in cells. We further show that MYC regulation by SNF5 is separable from its role in chromatin remodeling, and that reintroduction of SNF5 into SMARCB1-null cells mimics the primary transcriptional effects of MYC inhibition. These observations reveal that SNF5 antagonizes MYC and provide a mechanism to explain how loss of SNF5 can drive malignancy.