Truncation of GalNAc-type O-glycans Suppresses CD44-mediated Osteoclastogenesis and Bone Metastasis in Breast Cancer

Neng Yu Lin*, Jian Jr Lee, Syue Ting Chen, Jung An Lin, Chia Hsuan Lin, Hsuan Yu Lin, Yong Han Su, Cheng Chang Chen, Mei Chun Lin, Ching Ying Kuo, Min Chuan Huang

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

3 Scopus citations

Abstract

UNLABELLED: The glycoprotein CD44 is a key regulator of malignant behaviors in breast cancer cells. To date, hyaluronic acid (HA)-CD44 signaling pathway has been widely documented in the context of metastatic bone diseases. Core 1 β1,3-galactosyltransferase (C1GALT1) is a critical enzyme responsible for the elongation of O-glycosylation. Aberrant O-glycans is recognized as a hallmark in cancers. However, the effects of C1GALT1 on CD44 signaling and bone metastasis remain unclear. In this study, IHC analysis indicated that C1GALT1 expression positively correlates with CD44 in breast cancer. Silencing C1GALT1 accumulates the Tn antigen on CD44, which decreases CD44 levels and osteoclastogenic signaling. Mutations in the O-glycosites on the stem region of CD44 impair its surface localization as well as suppress cell-HA adhesion and osteoclastogenic effects of breast cancer cells. Furthermore, in vivo experiments demonstrated the inhibitory effect of silencing C1GALT1 on breast cancer bone metastasis and bone loss. In conclusion, our study highlights the importance of O-glycans in promoting CD44-mediated tumorigenic signals and indicates a novel function of C1GALT1 in driving breast cancer bone metastasis.

IMPLICATIONS: Truncation of GalNAc-type O-glycans by silencing C1GALT1 suppresses CD44-mediated osteoclastogenesis and bone metastasis in breast cancer. Targeting the O-glycans on CD44 may serve as a potential therapeutic target for blocking cancer bone metastasis.

Original languageEnglish
Pages (from-to)664-674
Number of pages11
JournalMolecular Cancer Research
Volume21
Issue number7
DOIs
StatePublished - 05 07 2023

Bibliographical note

©2023 The Authors; Published by the American Association for Cancer Research.

Keywords

  • Female
  • Humans
  • Breast Neoplasms/genetics
  • Glycosylation
  • Hyaluronan Receptors/genetics
  • Osteogenesis
  • Polysaccharides/metabolism
  • Signal Transduction

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