Interplay between transforming growth factor-? and Nur77 in dual regulations of inhibitor of differentiation 1 for colonic tumorigenesis.

The paradoxical roles of transforming growth factor-? (TGF?) signaling and nuclear receptor Nur77 in colon cancer development are known but the underlying mechanisms remain obscure. Inhibitor of differentiation 1 (ID1) is a target gene of TGF? and a key promoter for colon cancer progression. Here, we show that Nur77 enhances ...
TGF?/Smad3-induced ID1 mRNA expression through hindering Smurf2-mediated Smad3 mono-ubiquitylation, resulting in ID1 upregulation. In the absence of TGF?, however, Nur77 destabilizes ID1 protein by promoting Smurf2-mediated ID1 poly-ubiquitylation, resulting in ID1 downregulation. Interestingly, TGF? stabilizes ID1 protein by switching Nur77 interaction partners to inhibit ID1 ubiquitylation. This also endows TGF? with an active pro-tumorigenic action in Smad4-deficient colon cancers. Thus, TGF? converts Nur77's role from destabilizing ID1 protein and cancer inhibition to inducing ID1 mRNA expression and cancer promotion, which is highly relevant to colon cancer stemness, metastasis and oxaliplatin resistance. Our data therefore define the integrated duality of Nur77 and TGF? signaling in regulating ID1 expression and provide mechanistic insights into the paradoxical roles of TGF? and Nur77 in colon cancer progression.
Mesh Terms:
Animals, Carcinogenesis, Cell Line, Tumor, Colonic Neoplasms, Female, Gene Expression Regulation, Neoplastic, HCT116 Cells, HT29 Cells, Humans, Inhibitor of Differentiation Protein 1, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Models, Biological, Nuclear Receptor Subfamily 4, Group A, Member 1, Protein Stability, RNA, Messenger, Signal Transduction, Smad3 Protein, Smad4 Protein, Transforming Growth Factor beta, Ubiquitin-Protein Ligases, Ubiquitination
Nat Commun
Date: Dec. 14, 2020
Download Curated Data For This Publication
232425
Switch View:
  • Interactions 13