The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies.
The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies.
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DOI：
10.1038/ncomms14356
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发表时间：
2017-02-16
影响因子：
16.6
通讯作者：
Fu H
中科院分区：
文献类型：
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作者：
Li Z;Ivanov AA;Su R;Gonzalez-Pecchi V;Qi Q;Liu S;Webber P;McMillan E;Rusnak L;Pham C;Chen X;Mo X;Revennaugh B;Zhou W;Marcus A;Harati S;Chen X;Johns MA;White MA;Moreno C;Cooper LA;Du Y;Khuri FR;Fu H
随着基因组学的进步揭示了癌症基因的图景，一项艰巨的任务是了解这些基因是如何促进失调的致癌途径的。将癌症基因整合到网络中提供了揭示具有功能和治疗意义的蛋白质-蛋白质相互作用(PPI)的机会。在这里，我们报告了一个以癌症为中心的PPI网络的产生，称为OncoPPI，并鉴定了>；260个与癌症相关的PPI，这些与癌症相关的PPI不存在于其他大规模的互动中。PPI中枢揭示了MYC、STK11、RASSF1和CDK4等癌症基因的新调控机制。例如，NSD3(WHSC1L1)-MYC的相互作用表明了NSD3/BRD4染色质复合体调控MYC驱动的肿瘤的新机制。无法用药的肿瘤抑制因子与药物靶点的关联为治疗选择提供了信息。基于OncoPPI衍生的STK11-CDK4连接，我们观察到STK11沉默的肺癌细胞对FDA批准的CDK4抑制剂Palbociclib的敏感性增强。OncoPPI是一种专注于PPI的资源，它将癌症基因连接到一个信号网络，以发现PPI靶点和网络相关的肿瘤脆弱性，用于治疗询问。要了解癌症中的调控失调，除了癌症基因组之外，还需要了解癌症相关蛋白的相互作用。在这里，作者使用高通量、时间分辨的FRET来绘制蛋白质-蛋白质相互作用图，以建立肺癌蛋白质网络，并展示其在揭示新的致癌途径和肿瘤抑制因子与可药物靶点的连接方面的有效性。
As genomics advances reveal the cancer gene landscape, a daunting task is to understand how these genes contribute to dysregulated oncogenic pathways. Integration of cancer genes into networks offers opportunities to reveal protein–protein interactions (PPIs) with functional and therapeutic significance. Here, we report the generation of a cancer-focused PPI network, termed OncoPPi, and identification of >260 cancer-associated PPIs not in other large-scale interactomes. PPI hubs reveal new regulatory mechanisms for cancer genes like MYC, STK11, RASSF1 and CDK4. As example, the NSD3 (WHSC1L1)–MYC interaction suggests a new mechanism for NSD3/BRD4 chromatin complex regulation of MYC-driven tumours. Association of undruggable tumour suppressors with drug targets informs therapeutic options. Based on OncoPPi-derived STK11-CDK4 connectivity, we observe enhanced sensitivity of STK11-silenced lung cancer cells to the FDA-approved CDK4 inhibitor palbociclib. OncoPPi is a focused PPI resource that links cancer genes into a signalling network for discovery of PPI targets and network-implicated tumour vulnerabilities for therapeutic interrogation. Understanding of dysregulation in cancers requires knowledge, beyond cancer genomes, of the interactions of cancer-associated proteins. Here, the authors use high-throughput, time-resolved FRET to map protein–protein interactions to establish a lung cancer protein network, and demonstrate its utility in revealing new oncogenic pathways and connectivity of tumour suppressors with druggable targets.