Targeting BRD3 eradicates nuclear TYRO3-induced colorectal cancer metastasis

Sci Adv. 2023 Apr 14;9(15):eade3422. doi: 10.1126/sciadv.ade3422. Epub 2023 Apr 12.


Metastasis is the main cause of death in many cancers including colorectal cancer (CRC); however, the underlying mechanisms responsible for metastatic progression remain largely unknown. We found that nuclear TYRO3 receptor tyrosine kinase is a strong predictor of poor overall survival in patients with CRC. The metastasis-promoting function of nuclear TYRO3 requires its kinase activity and matrix metalloproteinase-2 (MMP-2)-mediated cleavage but is independent of ligand binding. Using proteomic analysis, we identified bromodomain-containing protein 3 (BRD3), an acetyl-lysine reading epigenetic regulator, as one of nuclear TYRO3's substrates. Chromatin immunoprecipitation-sequencing data reveal that TYRO3-phosphorylated BRD3 regulates genes involved in anti-apoptosis and epithelial-mesenchymal transition. Inhibition of MMP-2 or BRD3 activity by selective inhibitors abrogates nuclear TYRO3-induced drug resistance and metastasis in organoid culture and in orthotopic mouse models. These data demonstrate that MMP-2/TYRO3/BRD3 axis promotes the metastasis of CRC, and blocking this signaling cascade is a promising approach to ameliorate CRC malignancy.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • Colorectal Neoplasms* / pathology
  • Gene Expression Regulation, Neoplastic
  • Matrix Metalloproteinase 2* / genetics
  • Matrix Metalloproteinase 2* / metabolism
  • Mice
  • Neoplasm Metastasis
  • Proteomics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Matrix Metalloproteinase 2
  • Receptor Protein-Tyrosine Kinases
  • Transcription Factors
  • BRD3 protein, human
  • TYRO3 protein, human