Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion.
Jung Yun KimNayoung HongSehyeon ParkSeok Won HamEun-Jung KimSung-Ok KimJunseok JangYoonji KimJun-Kyum KimSung-Chan KimJong-Whi ParkHyunggee KimPublished in: Cell death & disease (2023)
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.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- signaling pathway
- cell migration
- induced apoptosis
- end stage renal disease
- gene expression
- reactive oxygen species
- transcription factor
- newly diagnosed
- chronic kidney disease
- ejection fraction
- cell cycle arrest
- cell proliferation
- pi k akt
- poor prognosis
- small molecule
- peritoneal dialysis
- prognostic factors
- oxidative stress
- cell death