JAG1 intracellular domain acts as a transcriptional cofactor that forms an oncogenic transcriptional complex with DDX17/SMAD3/TGIF2

Abstract

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, such as the formation of NOTCH1 intracellular domain (NICD1), however, the role of JICD1 in tumorigenicity has not been comprehensively elucidated. Herein, we revealed that JICD1 induced astrocytes to acquire several cancer stem cell properties, including tumor formation, invasiveness, stemness, and resistance to chemotherapy and radiotherapy. The transcriptome, ChIP-sequencing, and proteomic analyses revealed that JICD1 increased SOX2 expression by forming a transcriptional complex with DDX17, SMAD3, and TGIF2. Furthermore, JICD1-driven tumorigenicity was directly regulated by SOX2. Therefore, our results demonstrated that, like NICD1, JICD1 acts as a transcriptional cofactor in the formation of the DDX17/SMAD3/TGIF2 transcriptional complex, leading to oncogenic transformation.

Reversible and bidirectional signaling of notch ligands

“…Interestingly, JICD expression has an inverse correlation with the transcriptional factor Nur77, wherein the overexpression of J1ICD suppresses the activation of c-AMP induced by Nur77 in the cell line MA-10. Preliminary recent online reports show that JICD behaves as a transcriptional cofactor by complexing to DDX17, TGFI2, and Smad3 to promote Sox2 transcription (Kim et al 2021). Similarly, DLL1ICD modulates TGF-b signaling by interacting with the transcription factors Smad2, Smad3, and Smad4.…”

“…All the DSL ligands-ICDs are small molecules beneath 50 kDa (Figure 6); thus, passive diffusion to the cell nucleus is possible (Timney et al 2016). However, reports on ICDs interactions with cytoplasmic and nuclear proteins and the presence of nuclear localization sequences suggest that DSL ICD's nuclear translocation is controlled (Pintar et al 2007;D'Souza et al 2008;Kim et al 2021). Drosophila and human DSL ligands have conserved NLS (Ikeuchi and Sisodia 2003;Pintar et al 2007).…”

Jag1 Insufficiency Disrupts Neonatal T Cell Differentiation and Impairs Hepatocyte Maturation, Leading to Altered Liver Fibrosis

“…Whether loss of Jag1 signaling is protective or detrimental in ALGS, with regards to fibrosis, cirrhosis, and development of liver cancer, is controversial and not yet well understood [31][32][33][34][35]. Forty-eight percent (48%) of wild type C3H x C57bl6 male mice spontaneously develop liver tumors [64], indicating that the genetic background of Jag1 Ndr/Ndr C3H/C57bl6 mice is ideal for investigating whether Jag1 insufficiency is protective or detrimental [61,62].…”

“…However, the specific role for JAG1 in hepatitis, fibrosis, cirrhosis or carcinogenesis is unclear. Both up-regulation [31,32], and down-regulation [33,34] of JAG1 have been implicated in liver cancer, as well as noncanonical JAG1 intracellular domain effects [35]. Although ALGS is thought of as a Notch haploinsufficiency syndrome, until recently it was not clear if the ALGS patients are protected from HCC, or not [36].…”