The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies
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Nature Publishing Group
Abstract
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. © 2017 The Author(s).
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Cell line, tumor, Cell survival, Cyclin-dependent kinase 4, Databases, protein, Gene expression regulation, neoplastic, Gene regulatory networks, Genes, myc, Genes, tumor suppressor, Genomics, Histone-lysine n-methyltransferase, Humans, Lung neoplasms, Molecular targeted therapy, Neoplasm proteins, Nuclear proteins, Oncogenes, Protein interaction domains and motifs, Protein interaction mapping, Protein kinase inhibitors, Protein stability, Protein-serine-threonine kinases, Signal transduction, Transcription factors, Tumor suppressor proteins, Cyclin dependent kinase 4, Myc protein, Palbociclib, Protein kinase lkb1, Ras association domain family protein 1a, Brd4 protein, human, Cdk4 protein, human, Histone lysine methyltransferase, Nuclear protein, Protein kinase inhibitor, Protein serine threonine kinase, Rassf1 protein, human, Stk11 protein, human, Transcription factor, Tumor protein, Tumor suppressor protein, Whsc1l1 protein, human, Cancer, Cells and cell components, Drug, Gene, Inhibitor, Protein, Tumor, Article, Cancer genetics, Chromatin, Controlled study, Gene silencing, Human, Human cell, Information system, Protein protein interaction, Regulatory mechanism, Tumor gene, Tumor suppressor gene, Drug effect, Gene expression regulation, Gene regulatory network, Genetics, Lung tumor, Metabolism, Molecularly targeted therapy, Oncogene, Oncogene myc, Physiology, Protein analysis, Protein database, Protein domain, Tumor cell line