Post-transcriptional Control of Tumor Cell Autonomous Metastatic Potential by CCR4-NOT Deadenylase CNOT7.
Post-transcriptional Control of Tumor Cell Autonomous Metastatic Potential by CCR4-NOT Deadenylase CNOT7.
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DOI：
10.1371/journal.pgen.1005820
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发表时间：
2016-01
期刊：
影响因子：
4.5
通讯作者：
Hunter KW
中科院分区：
文献类型：
--
作者：
Faraji F;Hu Y;Yang HH;Lee MP;Winkler GS;Hafner M;Hunter KW
越来越多的证据支持异常转录组作为转移潜力驱动因素的作用。去腺苷化是 microRNA 和其他 RNA 稳定性决定因素进行转录后控制的通用调节节点。之前，我们证明了CCR4-NOT支架成分Cnot2是一种遗传性转移易感基因。在这项研究中，利用原位转移试验和基因工程小鼠模型，我们表明 CCR4-NOT 复合物的酶亚基之一 Cnot7 也是一种转移修饰基因。我们证明，Cnot7 的较高表达会驱动肿瘤细胞自主转移潜力，这需要其去腺苷酸酶活性。此外，CNOT7 的转移促进依赖于与 CNOT1 和 TOB1 的相互作用。 CNOT7 核糖核蛋白免疫沉淀 (RIP) 和综合转录组范围分析表明，CNOT7 调节的转录物富含由已知与 CNOT7、TOB1 和 CNOT1 复合的 RNA 结合蛋白结合的三联 3'UTR 基序。总的来说，我们的数据支持 CNOT7、TOB1、CNOT1 和 RNA 结合蛋白的模型，它们共同对转移抑制转录程序发挥转录后控制，以驱动肿瘤细胞转移。大多数人类癌症相关死亡是由于转移的影响、癌症扩散到远处器官和在远处器官生长的过程造成的。主要由于其复杂性，转移过程仍然不完全清楚。这种复杂性源于肿瘤细胞依赖多种细胞和分子系统来成功定植远处部位。在这项研究中，我们证明了导致转移进展的因素之一是肿瘤细胞 RNA 稳定性的控制。此前，我们证明CCR4-NOT转录调控复合物的结构成分是遗传性转移易感基因。在这里，我们证明 CCR-NOT 复合物的酶成分之一 Cnot7 也是一种转移相关基因，并且 Cnot7 的酶活性是其促进转移性疾病所必需的。这些结果表明，大规模控制 RNA 丰度可能会调节特定的转移相关转录程序，并且抑制特定的 RNA 去腺苷酶可能是开发抗转移疗法的可行途径。
Accumulating evidence supports the role of an aberrant transcriptome as a driver of metastatic potential. Deadenylation is a general regulatory node for post-transcriptional control by microRNAs and other determinants of RNA stability. Previously, we demonstrated that the CCR4-NOT scaffold component Cnot2 is an inherited metastasis susceptibility gene. In this study, using orthotopic metastasis assays and genetically engineered mouse models, we show that one of the enzymatic subunits of the CCR4-NOT complex, Cnot7, is also a metastasis modifying gene. We demonstrate that higher expression of Cnot7 drives tumor cell autonomous metastatic potential, which requires its deadenylase activity. Furthermore, metastasis promotion by CNOT7 is dependent on interaction with CNOT1 and TOB1. CNOT7 ribonucleoprotein-immunoprecipitation (RIP) and integrated transcriptome wide analyses reveal that CNOT7-regulated transcripts are enriched for a tripartite 3’UTR motif bound by RNA-binding proteins known to complex with CNOT7, TOB1, and CNOT1. Collectively, our data support a model of CNOT7, TOB1, CNOT1, and RNA-binding proteins collectively exerting post-transcriptional control on a metastasis suppressive transcriptional program to drive tumor cell metastasis. The majority of human cancer related death is due to the effects of metastasis, the process of cancer dissemination to and growth in distant organs. Primarily due to its complexity, the metastatic process remains incompletely understood. This complexity stems from the tumor cell’s dependence on multiple cellular and molecular systems for the successful colonization of distant sites. In this study, we demonstrate that one of the factors that contributes to metastatic progression is the control of tumor cell RNA stability. Previously, we demonstrated that a structural component of the CCR4-NOT transcription regulatory complex was an inherited metastasis susceptibility gene. Here we demonstrate that one of the enzymatic components of the CCR-NOT complex, Cnot7, is also a metastasis-associated gene, and that enzymatic activity of Cnot7 is required for its promotion of metastatic disease. These results suggest that large-scale control of RNA abundance may be modulating specific metastasis-related transcriptional programs, and that inhibition of specific RNA deadenylases may be a viable avenue in the development of anti-metastatic therapeutics.