Transition of Mesenchymal and Epithelial Cancer Cells Depends on α1-4 Galactosyltransferase-Mediated Glycosphingolipids

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Jacob, Francis
Alam, Shahidul
Konantz, Martina
Liang, Ching-Yeu
Kohler, Reto S
Everest-Dass, Arun V
Huang, Yen-Lin
Rimmer, Natalie
Fedier, Andre
Schotzau, Andreas
Lopez, Monica Nunez
Packer, Nicolle H
Lengerke, Claudia
Heinzelmann-Schwarz, Viola
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2018
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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 ΔA4GALT 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.

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Cancer Research

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78

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11

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Oncology and carcinogenesis

Oncology and carcinogenesis not elsewhere classified

Biochemistry and cell biology

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