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

Solaimuthu, B and Khatib, A and Tanna, M and Karmi, A and Hayashi, A and Rmaileh, AA and Lichtenstein, M and Takoe, S and Jolly, MK and Shaul, YD (2024) The exostosin glycosyltransferase 1/STAT3 axis is a driver of breast cancer aggressiveness. In: Proceedings of the National Academy of Sciences of the United States of America, 121 (3).

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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. © 2024 the Author(s).

Item Type:	Journal Article
Publication:	Proceedings of the National Academy of Sciences of the United States of America
Publisher:	National Academy of Sciences
Additional Information:	The copyright for this article belongs to National Academy of Sciences.
Keywords:	cyclophosphamide; estrogen receptor; exostosin glycosyltransferase 1; fibronectin; fluorouracil; gemcitabine; glycosyltransferase; interleukin 6; nerve cell adhesion molecule; progesterone receptor; proteoglycan; proteoheparan sulfate; STAT3 protein; Twist related protein 1; unclassified drug; vimentin; glycosyltransferase; STAT3 protein; STAT3 protein, human, A-549 cell line; aggressiveness; animal experiment; animal model; Article; bioluminescence; biosynthesis; breast cancer; cell invasion; cell migration; distant metastasis free survival; epithelial mesenchymal transition; female; fluorescence activated cell sorting; gene expression; gene set enrichment analysis; HCC827 cell line; Hs 578T cell line; human; human cell; immunohistochemistry; MCF-7 cell line; MDA-MB-157 cell line; MDA-MB-231 cell line; MDA-MB-468 cell line; mouse; NCI-H358 cell line; nonhuman; overall survival; signal transduction; single cell RNA seq; transcriptomics; ZR-75-1 cell line; breast tumor; cell line; cell motion; genetics; metabolism; tumor cell line, Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Female; Glycosyltransferases; Heparan Sulfate Proteoglycans; Humans; STAT3 Transcription Factor
Department/Centre:	Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited:	01 Mar 2024 09:11
Last Modified:	01 Mar 2024 09:11
URI:	https://eprints.iisc.ac.in/id/eprint/83972

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