A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis
A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis
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DOI：
10.1073/pnas.1100132108
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发表时间：
2011-10-25
影响因子：
11.1
通讯作者：
Davis, David P.
中科院分区：
文献类型：
--
作者：
Dompe, Nicholas;Rivers, Celina Sanchez;Davis, David P.
细胞凋亡的失调在癌症中是常见的，针对癌症，设计用于该途径的新兴肿瘤学治疗剂正在进行临床试验。为了揭示激活癌细胞凋亡的策略，我们使用了合并的shRNA筛选来询问死亡受体信号。该筛选方法鉴定了16个调节对配体诱导的细胞凋亡的敏感性的基因，其中几个基因在癌症中表现出频繁的过表达和/或拷贝数增加。有趣的是，两个最高的命中，EDD 1和GRHL 2，被发现在染色体8 q22上相隔50 kb，这是一个在许多癌症中经常扩增的区域。通过使用一系列的沉默和过表达的研究，我们表明，EDD 1和GRHL 2抑制死亡受体的表达，EDD 1的表达是升高的乳腺癌，胰腺癌和肺癌细胞系死亡受体介导的凋亡。支持EDD 1和GRHL 2作为参与癌细胞凋亡的治疗候选物的相关性，沉默任一基因的表达使8 q22扩增的乳腺癌细胞系对死亡受体诱导的凋亡敏感。我们的研究结果强调了癌细胞可能逃避凋亡的机制，因此为寻找该途径的新靶点和功能性生物标志物提供了见解。
Deregulation of apoptosis is a common occurrence in cancer, for which emerging oncology therapeutic agents designed to engage this pathway are undergoing clinical trials. With the aim of uncovering strategies to activate apoptosis in cancer cells, we used a pooled shRNA screen to interrogate death receptor signaling. This screening approach identified 16 genes that modulate the sensitivity to ligand induced apoptosis, with several genes exhibiting frequent overexpression and/or copy number gain in cancer. Interestingly, two of the top hits, EDD1 and GRHL2, are found 50 kb apart on chromosome 8q22, a region that is frequently amplified in many cancers. By using a series of silencing and overexpression studies, we show that EDD1 and GRHL2 suppress death-receptor expression, and that EDD1 expression is elevated in breast, pancreas, and lung cancer cell lines resistant to death receptor-mediated apoptosis. Supporting the relevance of EDD1 and GRHL2 as therapeutic candidates to engage apoptosis in cancer cells, silencing the expression of either gene sensitizes 8q22-amplified breast cancer cell lines to death receptor induced apoptosis. Our findings highlight a mechanism by which cancer cells may evade apoptosis, and therefore provide insight in the search for new targets and functional biomarkers for this pathway.