p53-Pirh2 Complex Promotes Twist1 Degradation and Inhibits EMT

Mol Cancer Res. 2019 Jan;17(1):153-164. doi: 10.1158/1541-7786.MCR-18-0238. Epub 2018 Aug 21.


Epithelial-mesenchymal transition (EMT) is a critical process involved in cancer metastasis and chemoresistance. Twist1 is a key EMT-inducing transcription factor, which is upregulated in multiple types of cancers and has been shown to promote tumor cell invasiveness and support tumor progression. Conversely, p53 is a tumor suppressor gene that is frequently mutated in cancers. This study demonstrates the ability of wild-type (WT) p53 to promote the degradation of Twist1 protein. By forming a complex with Twist1 and the E3 ligase Pirh2, WT p53 promotes the ubiquitination and proteasomal degradation of Twist1, thus inhibiting EMT and maintaining the epithelial phenotype. The ability of p53 to induce Twist1 degradation is abrogated when p53 is mutated. Consequently, the loss of p53-induced Twist1 degradation leads to EMT and the acquisition of a more invasive cancer phenotype.Implication: These data provide new insight into the metastatic process at the molecular level and suggest a signaling pathway that can potentially be used to develop new prognostic markers and therapeutic targets to curtail cancer progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / metabolism
  • Cystadenocarcinoma, Serous / pathology
  • Epithelial-Mesenchymal Transition
  • Female
  • HEK293 Cells
  • Humans
  • Mutation
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Twist-Related Protein 1 / biosynthesis
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*


  • Nuclear Proteins
  • TP53 protein, human
  • TWIST1 protein, human
  • Tumor Suppressor Protein p53
  • Twist-Related Protein 1
  • RCHY1 protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex