Apical-basal polarity inhibits epithelial-mesenchymal transition and tumour metastasis by PAR-complex-mediated SNAI1 degradation

Nat Cell Biol. 2019 Mar;21(3):359-371. doi: 10.1038/s41556-019-0291-8. Epub 2019 Feb 25.

Abstract

Loss of apical-basal polarity and activation of epithelial-mesenchymal transition (EMT) both contribute to carcinoma progression and metastasis. Here, we report that apical-basal polarity inhibits EMT to suppress metastatic dissemination. Using mouse and human epithelial three-dimensional organoid cultures, we show that the PAR-atypical protein kinase C (aPKC) polarity complex inhibits EMT and invasion by promoting degradation of the SNAIL family protein SNAI1. Under intact apical-basal polarity, aPKC kinases phosphorylate S249 of SNAI1, which leads to protein degradation. Loss of apical-basal polarity prevents aPKC-mediated SNAI1 phosphorylation and stabilizes the SNAI1 protein to promote EMT and invasion. In human breast tumour xenografts, inhibition of the PAR-complex-mediated SNAI1 degradation mechanism promotes tumour invasion and metastasis. Analyses of human breast tissue samples reveal negative correlations between PAR3 and SNAI1 protein levels. Our results demonstrate that apical-basal polarity functions as a critical checkpoint of EMT to precisely control epithelial-mesenchymal plasticity during tumour metastasis.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Caco-2 Cells
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Polarity*
  • Epithelial-Mesenchymal Transition*
  • Female
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mice, Transgenic
  • Multiprotein Complexes / metabolism*
  • Neoplasm Metastasis
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Protein Kinase C / metabolism
  • Proteolysis
  • RNA Interference
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism*
  • Transplantation, Heterologous

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Membrane Proteins
  • Multiprotein Complexes
  • PARD3 protein, human
  • PARD6A protein, human
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • PKC-3 protein
  • Protein Kinase C