Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion

Autor: Jung Yun Kim, Nayoung Hong, Sehyeon Park, Seok Won Ham, Eun-Jung Kim, Sung-Ok Kim, Junseok Jang, Yoonji Kim, Jun-Kyum Kim, Sung-Chan Kim, Jong-Whi Park, Hyunggee Kim
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Cell Death and Disease, Vol 14, Iss 12, Pp 1-13 (2023)
Druh dokumentu: article
ISSN: 2041-4889
DOI: 10.1038/s41419-023-06356-0
Popis: Abstract Jagged1 (JAG1) is a Notch ligand that correlates with tumor progression. Not limited to its function as a ligand, JAG1 can be cleaved, and its intracellular domain translocates to the nucleus, where it functions as a transcriptional cofactor. Previously, we showed that JAG1 intracellular domain (JICD1) forms a protein complex with DDX17/SMAD3/TGIF2. However, the molecular mechanisms underlying JICD1-mediated tumor aggressiveness remains unclear. Here, we demonstrate that JICD1 enhances the invasive phenotypes of glioblastoma cells by transcriptionally activating epithelial-to-mesenchymal transition (EMT)-related genes, especially TWIST1. The inhibition of TWIST1 reduced JICD1-driven tumor aggressiveness. Although SMAD3 is an important component of transforming growth factor (TGF)-β signaling, the JICD1/SMAD3 transcriptional complex was shown to govern brain tumor invasion independent of TGF-β signaling. Moreover, JICD1-TWIST1-MMP2 and MMP9 axes were significantly correlated with clinical outcome of glioblastoma patients. Collectively, we identified the JICD1/SMAD3-TWIST1 axis as a novel inducer of invasive phenotypes in cancer cells.
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