Expression inactivation of SMARCA4 by microRNAs in lung tumors
Expression inactivation of SMARCA4 by microRNAs in lung tumors
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DOI：
10.1093/hmg/ddu554
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发表时间：
2015-03-01
影响因子：
3.5
通讯作者：
Medina, Pedro P.
中科院分区：
文献类型：
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作者：
Coira, Isabel F.;Rufino-Palomares, Eva E.;Medina, Pedro P.
SMARCA4是SWI/SNF染色质重塑复合体的催化亚基，它改变DNA和组蛋白之间的相互作用，并修饰DNA的转录可用性。最新的肿瘤基因组深度测序强化了SWI/SNF复合物在肿瘤中的重要和普遍的抑癌作用。然而，尽管SWI/SNF复合物在基因表达中起着关键作用，但对该复合物本身的调控却知之甚少。值得注意的是，对SMARCA4表达调控的理解变得越来越重要，因为最近有人建议将其纳入使用SMARCA4- max和SMARCA4- smarca2之间合成致死相互作用的治疗策略中。在本报告中，我们发现在一些原发性肺肿瘤中观察到的SMARCA4的表达缺失，其机制在很大程度上是未知的，至少部分可以通过microRNAs （miRNAs）的活性来解释。我们发现SMARCA4的表达受miR-101， miR-199，尤其是miR-155的调控，通过它们与两个可选的3' utr的结合。重要的是，我们的实验表明miR-155在肺癌中的致癌特性在很大程度上可以通过其抑制SMARCA4的作用来解释。这一新发现的功能关系可以解释独立高miR-155和低SMARCA4表达水平的患者表现出的不良预后。此外，这些结果可能导致早期miRNA技术应用于上述合成致死治疗策略。
SMARCA4 is the catalytic subunit of the SWI/SNF chromatin-remodeling complex, which alters the interactions between DNA and histones and modifies the availability of the DNA for transcription. The latest deep sequencing of tumor genomes has reinforced the important and ubiquitous tumor suppressor role of the SWI/SNF complex in cancer. However, although SWI/SNF complex plays a key role in gene expression, the regulation of this complex itself is poorly understood. Significantly, an understanding of the regulation of SMARCA4 expression has gained in importance due to recent proposals incorporating it in therapeutic strategies that use synthetic lethal interactions between SMARCA4-MAX and SMARCA4-SMARCA2. In this report, we found that the loss of expression of SMARCA4 observed in some primary lung tumors, whose mechanism was largely unknown, can be explained, at least partially by the activity of microRNAs (miRNAs). We reveal that SMARCA4 expression is regulated by miR-101, miR-199 and especially miR-155 through their binding to two alternative 3'UTRs. Importantly, our experiments suggest that the oncogenic properties of miR-155 in lung cancer can be largely explained by its role inhibiting SMARCA4. This new discovered functional relationship could explain the poor prognosis displayed by patients that independently have high miR-155 and low SMARCA4 expression levels. In addition, these results could lead to application of incipient miRNA technology to the aforementioned synthetic lethal therapeutic strategies.