Jagged1 (JAG1) is a Notch ligand that contact-dependently activates Notch receptors and regulates cancer progression. The JAG1 intracellular domain (JICD1) is generated from JAG1, like formation of the NOTCH1 intracellular domain (NICD1); however, the role of JICD1 in tumorigenicity has not been comprehensively elucidated. Here we show that JICD1 induces astrocytes to acquire several cancer stem cell properties, including tumor formation, invasiveness, stemness, and resistance to anticancer therapy. The transcriptome, chromatin immunoprecipitation sequencing (ChIP-seq), and proteomics analyses show that JICD1 increases SOX2 expression by forming a transcriptional complex with DDX17, SMAD3, and TGIF2. JICD1-driven tumorigenicity is directly regulated by SOX2. Our results demonstrate that, like NICD1, JICD1 acts as a transcriptional cofactor in formation of the DDX17/SMAD3/TGIF2 transcriptional complex, leading to oncogenic transformation.
|Publication status||Published - 2022 Nov 22|
Bibliographical noteFunding Information:
We thank all members of the Cancer Growth Regulation Lab for supportive discussions and technical assistance. We thank Dr. Didier Auboeuf (Centre Léon Bérard, Lyon, France) for providing the DDX17 vector and Dr. Jonghwan Kim (University of Texas at Austin, Austin, TX, USA) for supplying the shTgif1 vector. The biospecimens and data used for this study were provided by the Biobank of Chungnam National University Hospital (Daejeon, South Korea). This study was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Education ( 2020R1A2C2099668 and 2022M3E5F2018255 to H.K., 2016R1D1A1B03934783 to S.-C.K., 2016R1D1A1B03931941 to S.-H.K., and 2016M3C7A1913844 to S.H.K.) and the School of Life Sciences and Biotechnology for BK21 Plus, Korea University.
© 2022 The Authors
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)