The exostosin glycosyltransferase 1/STAT3 axis is a driver of breast cancer aggressiveness

Balakrishnan Solaimuthu, Anees Khatib, Mayur Tanna, Abdelrahman Karmi, Arata Hayashi, Areej Abu Rmaileh, Michal Lichtenstein, Suranjana Takoe, Mohit Kumar Jolly, Yoav David Shaul*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The epithelial-mesenchymal transition (EMT) program is crucial for transforming carcinoma cells into a partially mesenchymal state, enhancing their chemoresistance, migration, and metastasis. This shift in cell state is tightly regulated by cellular mechanisms that are not yet fully characterized. One intriguing EMT aspect is the rewiring of the proteoglycan landscape, particularly the induction of heparan sulfate proteoglycan (HSPG) biosynthesis. This proteoglycan functions as a co-receptor that accelerates cancer-associated signaling pathways through its negatively-charged residues. However, the precise mechanisms through which EMT governs HSPG biosynthesis and its role in cancer cell plasticity remain elusive. Here, we identified exostosin glycosyltransferase 1 (EXT1), a central enzyme in HSPG biosynthesis, to be selectively upregulated in aggressive tumor subtypes and cancer cell lines, and to function as a key player in breast cancer aggressiveness. Notably, ectopic expression of EXT1 in epithelial cells is sufficient to induce HSPG levels and the expression of known mesenchymal markers, subsequently enhancing EMT features, including cell migration, invasion, and tumor formation. Additionally, EXT1 loss in MDA-MB- 231 cells inhibits their aggressiveness-associated traits such as migration, chemoresistance, tumor formation, and metastasis. Our findings reveal that EXT1, through its role in HSPG biosynthesis, governs signal transducer and activator of transcription 3 (STAT3) signaling, a known regulator of cancer cell aggressiveness. Collectively, we present the EXT1/HSPG/STAT3 axis as a central regulator of cancer cell plasticity that directly links proteoglycan synthesis to oncogenic signaling pathways.

Original languageAmerican English
Article numbere2316733121
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number3
DOIs
StatePublished - 16 Jan 2024

Bibliographical note

Publisher Copyright:
© 2024 the Author(s).

Keywords

  • STAT3 signaling
  • breast cancer
  • epithelial-mesenchymal transition
  • exostosin glycosyltransferase 1
  • heparan sulfate

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