The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies

Nat Commun. 2017 Feb 16;8:14356. doi: 10.1038/ncomms14356.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Databases, Protein
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / genetics*
  • Gene Regulatory Networks / drug effects*
  • Gene Regulatory Networks / genetics*
  • Genes, Tumor Suppressor / drug effects
  • Genes, myc / genetics
  • Genomics
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Molecular Targeted Therapy
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oncogenes / drug effects*
  • Oncogenes / genetics*
  • Oncogenes / physiology
  • Protein Interaction Domains and Motifs / drug effects*
  • Protein Interaction Domains and Motifs / genetics*
  • Protein Interaction Domains and Motifs / physiology
  • Protein Interaction Mapping
  • Protein Kinase Inhibitors / pharmacology
  • Protein Stability
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • RASSF1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Histone-Lysine N-Methyltransferase
  • NSD3 protein, human
  • STK11 protein, human
  • Protein-Serine-Threonine Kinases
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4