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Targeting BRD3 eradicates nuclear TYRO3-induced colorectal cancer metastasis
Pei-Ling Hsu1,2, Chun-Wei Chien3, Yen-An Tang4
1Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Abstract:
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.
Insights
Nuclear TYRO3 receptor tyrosine kinase drives colorectal cancer (CRC) metastasis by activating the MMP-2/BRD3 axis. Inhibiting this pathway offers a promising strategy to combat CRC progression and drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Metastasis is the primary cause of cancer mortality, particularly in colorectal cancer (CRC).
- The molecular mechanisms driving metastatic progression in CRC are not fully understood.
- Nuclear TYRO3 receptor tyrosine kinase has been identified as a potential prognostic marker in CRC.
Purpose of the Study:
- To elucidate the role of nuclear TYRO3 in colorectal cancer metastasis.
- To identify downstream targets and signaling pathways regulated by nuclear TYRO3.
- To evaluate the therapeutic potential of targeting the TYRO3 signaling axis in CRC.
Main Methods:
- Proteomic analysis to identify substrates of nuclear TYRO3.
- Chromatin immunoprecipitation-sequencing (ChIP-seq) to determine BRD3-regulated genes.
- Inhibition studies using selective inhibitors of MMP-2 and BRD3 in organoid and mouse models.
Main Results:
- Nuclear TYRO3 promotes CRC metastasis through kinase activity and MMP-2 cleavage, independent of ligand binding.
- Bromodomain-containing protein 3 (BRD3) was identified as a substrate of TYRO3; TYRO3-phosphorylated BRD3 regulates genes involved in anti-apoptosis and epithelial-mesenchymal transition.
- Inhibition of MMP-2 or BRD3 abrogated nuclear TYRO3-induced drug resistance and metastasis in preclinical models.
Conclusions:
- The MMP-2/TYRO3/BRD3 signaling axis is a critical driver of colorectal cancer metastasis and drug resistance.
- Targeting this axis represents a promising therapeutic strategy to reduce CRC malignancy.
- Nuclear TYRO3 is a significant predictor of poor survival in CRC patients.
