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O-linked mucin-type glycosylation regulates the transcriptional programme downstream of EGFR

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Virginia Tajadura-Ortega, Gennaro Gambardella, Alexandra Skinner, Adnan Halim, Julie Van Coillie, Katrine Ter-Borch Gram Schjoldager, Richard Beatson, Rosalind Graham, Daniela Achkova, Joyce Taylor-Papadimitriou, Francesca D Ciccarelli, Joy M Burchell

Original languageEnglish
JournalGlycobiology
DOIs
E-pub ahead of print8 Aug 2020

Bibliographical note

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

King's Authors

Abstract

Aberrant mucin type O-linked glycosylation is a common occurrence in cancer where the upregulation of sialyltransferases is often seen leading to early termination of O-glycan chains. Mucin type O-linked glycosylation is not limited to mucins and occurs on many cell surface glycoproteins including EGFR, where the number of sites can be limited. Upon EGF ligation, EGFR induces a signalling cascade and may also translocate to the nucleus where it directly regulates gene transcription, a process modulated by Galectin-3 and MUC1 in some cancers. Here we show that upon EGF binding, breast cancer cells carrying different O-glycans respond by transcribing different gene expression signatures. MMP10, the principal gene upregulated when cells carrying sialylated core 1 glycans were stimulated with EGF, is also upregulated in ER positive breast carcinoma reported to express high levels of ST3Gal1 and hence mainly core 1 sialylated O-glycans. In contrast, isogenic cells engineered to carry core 2 glycans upregulate CX3CL1 and FGFBP1 and these genes are upregulated in ER negative breast carcinomas, also known to express longer core 2 O-glycans. Changes in O-glycosylation did not significantly alter signal transduction downstream of EGFR in core 1 or core 2 O-glycan expressing cells. However, striking changes were observed in the formation of an EGFR/galectin-3/MUC1/β-catenin complex at the cell surface that is present in cells carrying short core 1-based O-glycans but absent in core 2 carrying cells.

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