Targeting BRD3 eradicates nuclear TYRO3-induced colorectal cancer metastasis

Pei Ling Hsu, Chun Wei Chien, Yen An Tang, Bo Wen Lin, Shih Chieh Lin, Yi Syuan Lin, Sih Yu Chen, H. Sunny Sun, Shaw Jenq Tsai

研究成果: Article同行評審

6 引文 斯高帕斯(Scopus)

摘要

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.

原文English
文章編號eade3422
期刊Science Advances
9
發行號15
DOIs
出版狀態Published - 2023 4月

All Science Journal Classification (ASJC) codes

  • 多學科

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