| First Author | Niu B | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 2809 |
| PubMed ID | 33990575 | Mgi Jnum | J:319807 |
| Mgi Id | MGI:6713875 | Doi | 10.1038/s41467-021-23048-5 |
| Citation | Niu B, et al. (2021) Interplay between transforming growth factor-beta and Nur77 in dual regulations of inhibitor of differentiation 1 for colonic tumorigenesis. Nat Commun 12(1):2809 |
| abstractText | The paradoxical roles of transforming growth factor-beta (TGFbeta) 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 TGFbeta and a key promoter for colon cancer progression. Here, we show that Nur77 enhances TGFbeta/Smad3-induced ID1 mRNA expression through hindering Smurf2-mediated Smad3 mono-ubiquitylation, resulting in ID1 upregulation. In the absence of TGFbeta, however, Nur77 destabilizes ID1 protein by promoting Smurf2-mediated ID1 poly-ubiquitylation, resulting in ID1 downregulation. Interestingly, TGFbeta stabilizes ID1 protein by switching Nur77 interaction partners to inhibit ID1 ubiquitylation. This also endows TGFbeta with an active pro-tumorigenic action in Smad4-deficient colon cancers. Thus, TGFbeta 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 TGFbeta signaling in regulating ID1 expression and provide mechanistic insights into the paradoxical roles of TGFbeta and Nur77 in colon cancer progression. |
