Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer

EBioMedicine. 2016 Jun;8:159-172. doi: 10.1016/j.ebiom.2016.05.003. Epub 2016 May 5.

Abstract

Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, albeit, their functions are elusive. To assess the so far unknown role of DOK1 in colorectal cancer (CRC), we generated DOK1 mutants which mimic the domain structure and subcellular distribution of DOK1 protein variants in leukemia patients. We found that cytoplasmic DOK1 activated peroxisome-proliferator-activated-receptor-gamma (PPARγ) resulting in inhibition of the c-FOS promoter and cell proliferation, whereas nuclear DOK1 was inactive. PPARγ-agonist increased expression of endogenous DOK1 and interaction with PPARγ. Forward translation of this cell-based signaling model predicted compartmentalization of DOK1 in patients. In a large series of CRC patients, loss of DOK1 protein was associated with poor prognosis at early tumor stages (*p=0.001; n=1492). In tumors with cytoplasmic expression of DOK1, survival was improved, whereas nuclear localization of DOK1 correlated with poor outcome, indicating that compartmentalization of DOK1 is critical for CRC progression. Thus, DOK1 was identified as a prognostic factor for non-metastatic CRC, and, via its drugability by PPARγ-agonist, may constitute a potential target for future cancer treatments.

Keywords: Colorectal cancer; DOK; Docking protein; PPAR; RAS.

MeSH terms

  • Biomarkers
  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Progression
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Space / metabolism
  • Ligands
  • Mutation
  • Neoplasm Metastasis
  • Neoplasm Staging
  • PPAR gamma / metabolism
  • Phosphoproteins / chemistry
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Prognosis
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • Proto-Oncogene Proteins c-fos / genetics
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Survival Analysis
  • Transcriptional Activation

Substances

  • Biomarkers
  • DNA-Binding Proteins
  • DOK1 protein, human
  • Ligands
  • PPAR gamma
  • Phosphoproteins
  • Proto-Oncogene Proteins c-fos
  • RNA-Binding Proteins