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

Nat Commun. 2021 May 14;12(1):2809. doi: 10.1038/s41467-021-23048-5.


The paradoxical roles of transforming growth factor-β (TGFβ) 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 TGFβ and a key promoter for colon cancer progression. Here, we show that Nur77 enhances TGFβ/Smad3-induced ID1 mRNA expression through hindering Smurf2-mediated Smad3 mono-ubiquitylation, resulting in ID1 upregulation. In the absence of TGFβ, however, Nur77 destabilizes ID1 protein by promoting Smurf2-mediated ID1 poly-ubiquitylation, resulting in ID1 downregulation. Interestingly, TGFβ stabilizes ID1 protein by switching Nur77 interaction partners to inhibit ID1 ubiquitylation. This also endows TGFβ with an active pro-tumorigenic action in Smad4-deficient colon cancers. Thus, TGFβ 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 TGFβ signaling in regulating ID1 expression and provide mechanistic insights into the paradoxical roles of TGFβ and Nur77 in colon cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis
  • Cell Line, Tumor
  • Colonic Neoplasms / etiology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Inhibitor of Differentiation Protein 1 / genetics
  • Inhibitor of Differentiation Protein 1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Models, Biological
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Protein Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Smad3 Protein / metabolism
  • Smad4 Protein / deficiency
  • Smad4 Protein / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination


  • ID1 protein, human
  • Inhibitor of Differentiation Protein 1
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • RNA, Messenger
  • SMAD3 protein, human
  • SMAD4 protein, human
  • Smad3 Protein
  • Smad4 Protein
  • Transforming Growth Factor beta
  • SMURF2 protein, human
  • Ubiquitin-Protein Ligases