| First Author | Hsu PL | Year | 2023 |
| Journal | Sci Adv | Volume | 9 |
| Issue | 15 | Pages | eade3422 |
| PubMed ID | 37043564 | Mgi Jnum | J:334756 |
| Mgi Id | MGI:7463425 | Doi | 10.1126/sciadv.ade3422 |
| Citation | Hsu PL, et al. (2023) Targeting BRD3 eradicates nuclear TYRO3-induced colorectal cancer metastasis. Sci Adv 9(15):eade3422 |
| abstractText | 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. |
