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

• Published in: Nature cell biology Vol. 21; no. 3; pp. 359 - 371
• Main Authors: Jung, Hae-Yun, Fattet, Laurent, Tsai, Jeff H., Kajimoto, Taketoshi, Chang, Qiang, Newton, Alexandra C., Yang, Jing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2019; Nature Publishing Group
• Subjects: 13/106; 13/51; 14; 14/105; 14/19; 631/80/84/2176; 631/80/84/2336; 631/80/85; 64; 64/110; 64/60; 692/699/67/1347; 82; 82/51; 96/95; Adaptor Proteins, Signal Transducing - metabolism; Analysis; Animals; Biodegradation; Breast cancer; Caco-2 Cells; Cancer; Cancer metastasis; Cancer Research; Carcinoma; Cell Biology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell physiology; Cell Polarity; Cytological research; Degradation; Development and progression; Developmental Biology; Epithelial-Mesenchymal Transition; Female; Health aspects; Humans; Kinases; Life Sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mesenchyme; Metastases; Metastasis; Mice, Inbred BALB C; Mice, Nude; Mice, Transgenic; Multiprotein Complexes - metabolism; Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Organoids; Phosphorylation; Physiological aspects; Polarity; Protein kinase C; Protein Kinase C - metabolism; Protein kinases; Proteins; Proteolysis; RNA Interference; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Snail protein; Stem Cells; Tetracyclines; Transcription factors; Transplantation, Heterologous; Tumors; Xenografts; Xenotransplantation
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-019-0291-8

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. Jung et al. demonstrate, using 3D organoid cultures, that the PAR–aPKC polarity complex counteracts epithelial–mesenchymal transition and invasion through phosphorylation-dependent regulation of SNAI1 stability.