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p53-Pirh2 Complex Promotes Twist1 Degradation and Inhibits EMT

Yang Yang-Hartwich1, Roslyn Tedja1, Cai M Roberts2

  • 1Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.

Molecular Cancer Research : MCR
|August 23, 2018
PubMed

Insights

Wild-type p53 degrades Twist1 protein, inhibiting cancer metastasis. Loss of this p53 function in mutated cancers promotes tumor invasiveness and progression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Epithelial-mesenchymal transition (EMT) drives cancer metastasis and chemoresistance.
  • Twist1 is a key transcription factor promoting EMT, invasiveness, and tumor progression.
  • p53, a tumor suppressor, is frequently mutated in cancers.

Purpose of the Study:

  • To investigate the role of wild-type p53 in regulating Twist1 protein.
  • To elucidate the mechanism by which p53 affects Twist1 during cancer progression.

Main Methods:

  • Investigated the interaction between wild-type p53, Twist1, and the E3 ligase Pirh2.
  • Assessed the ubiquitination and proteasomal degradation of Twist1.
  • Examined the impact of p53 mutation on Twist1 degradation and EMT.

Main Results:

  • Wild-type p53 forms a complex with Twist1 and Pirh2, promoting Twist1 ubiquitination and degradation.
  • p53-mediated Twist1 degradation inhibits EMT and maintains the epithelial phenotype.
  • Mutated p53 loses the ability to induce Twist1 degradation, leading to EMT.

Conclusions:

  • p53 acts as a crucial regulator of Twist1 stability, thereby controlling EMT.
  • The loss of p53's ability to degrade Twist1 contributes to cancer cell invasiveness and progression.
  • This pathway presents potential therapeutic targets for inhibiting cancer metastasis.

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