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

Balakrishnan Solaimuthu1, Anees Khatib1, Mayur Tanna1

  • 1Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel.

Proceedings of the National Academy of Sciences of the United States of America
|January 12, 2024
PubMed

Insights

Exostosin glycosyltransferase 1 (EXT1) drives cancer cell plasticity by boosting heparan sulfate proteoglycan (HSPG) synthesis, promoting metastasis and chemoresistance through STAT3 signaling.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Cellular Plasticity

Background:

  • Epithelial-mesenchymal transition (EMT) enhances cancer cell migration, metastasis, and chemoresistance.
  • Heparan sulfate proteoglycans (HSPGs) act as co-receptors, accelerating cancer-associated signaling.
  • Mechanisms linking EMT, HSPG biosynthesis, and cancer cell plasticity are not fully understood.

Purpose of the Study:

  • To investigate the role of exostosin glycosyltransferase 1 (EXT1) in EMT and cancer aggressiveness.
  • To elucidate the molecular mechanisms by which EXT1 influences cancer cell plasticity and oncogenic signaling.

Main Methods:

  • Analysis of EXT1 expression in aggressive tumor subtypes and cell lines.
  • Ectopic expression of EXT1 in epithelial cells to assess EMT induction.
  • Loss-of-function studies of EXT1 in MDA-MB-231 breast cancer cells.
  • Investigation of the link between EXT1, HSPG biosynthesis, and STAT3 signaling.

Main Results:

  • EXT1 is selectively upregulated in aggressive tumors and enhances breast cancer aggressiveness.
  • Ectopic EXT1 expression induces HSPG levels, mesenchymal markers, and EMT features (migration, invasion, tumor formation).
  • EXT1 loss inhibits migration, chemoresistance, tumor formation, and metastasis in MDA-MB-231 cells.
  • EXT1 regulates STAT3 signaling, a key driver of cancer cell aggressiveness.

Conclusions:

  • EXT1 is a critical regulator of cancer cell plasticity, linking proteoglycan synthesis to oncogenic signaling.
  • The EXT1/HSPG/STAT3 axis represents a novel therapeutic target for modulating cancer cell aggressiveness.
Keywords:
STAT3 signalingbreast cancerepithelial-mesenchymal transitionexostosin glycosyltransferase 1heparan sulfate

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