Transition of mesenchymal and epithelial cancer cells depends on α1-4 galactosyltransferase-mediated glycosphingolipids

Francis Jacob*, Shahidul Alam, Martina Konantz, Ching Yeu Liang, Reto S. Kohler, Arun V. Everest-Dass, Yen-Lin Huang, Natalie Rimmer, Andre Fedier, Andreas Schötzau, Monica Nunez Lopez, Nicolle H. Packer, Claudia Lengerke, Viola Heinzelmann-Schwarz

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The reversible transitions of cancer cells between epithelial and mesenchymal states comprise cellular and molecular processes essential for local tumor growth and respective dissemination. We report here that globoside glycosphingolipid (GSL) glycosyltransferase-encoding genes are elevated in epithelial cells and correlate with characteristic EMT signatures predictive of disease outcome. Depletion of globosides through CRISPR-Cas9–mediated deletion of the key enzyme A4GALT induces EMT, enhances chemoresistance, and increased CD24low/CD44high cells. The cholera toxin–induced mesenchymal-to-epithelial transition occurred only in cells with functional A4GALT. Cells undergoing EMT lost E-cadherin expression through epigenetic silencing at the promoter region of CDH1. However, in DA4GALT cells, demethylation was able to rescue E-cadherin–mediated cell–cell adhesion only in the presence of exogenous A4GALT. Overall, our data suggest another class of biomolecules vital for epithelial cancer cells and for maintaining cell integrity and function.

Significance: This study highlights the essential role of glycosphingolipids in the maintenance of epithelial cancer cell properties.

Original languageEnglish
Pages (from-to)2952-2965
Number of pages14
JournalCancer Research
Volume78
Issue number11
DOIs
Publication statusPublished - 1 Jun 2018

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