Sulfated Hyaluronan Binds to Heparanase and Blocks Its Enzymatic and Cellular Actions in Carcinoma Cells

Jia Shi, Riku Kanoya, Yurina Tani, Sodai Ishikawa, Rino Maeda, Sana Suzuki, Fumiya Kawanami, Naoko Miyagawa, Katsuhiko Takahashi, Teruaki Oku, Ami Yamamoto, Kaori Fukuzawa, Motowo Nakajima, Tatsuro Irimura, Nobuaki Higashi

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1 Citation (Scopus)


We examined whether sulfated hyaluronan exerts inhibitory effects on enzymatic and biological actions of heparanase, a sole endo-beta-glucuronidase implicated in cancer malignancy and inflammation. Degradation of heparan sulfate by human and mouse heparanase was inhibited by sulfated hyaluronan. In particular, high-sulfated hyaluronan modified with approximately 2.5 sulfate groups per disaccharide unit effectively inhibited the enzymatic activity at a lower concentra-tion than heparin. Human and mouse heparanase bound to immobilized sulfated hyaluronan. Invasion of heparanase-positive colon-26 cells and 4T1 cells under 3D culture conditions was signifi-cantly suppressed in the presence of high-sulfated hyaluronan. Heparanase-induced release of CCL2 from colon-26 cells was suppressed in the presence of sulfated hyaluronan via blocking of cell surface binding and subsequent intracellular NF-κB-dependent signaling. The inhibitory effect of sulfated hyaluronan is likely due to competitive binding to the heparanase molecule, which antag-onizes the heparanase-substrate interaction. Fragment molecular orbital calculation revealed a strong binding of sulfated hyaluronan tetrasaccharide to the heparanase molecule based on electro-static interactions, particularly characterized by interactions of (−1)-and (−2)-positioned sulfated sugar residues with basic amino acid residues composing the heparin-binding domain-1 of hepara-nase. These results propose a relevance for sulfated hyaluronan in the blocking of heparanase-me-diated enzymatic and cellular actions.

Original languageEnglish
Article number5055
JournalInternational Journal of Molecular Sciences
Issue number9
Publication statusPublished - 2022 May 1


  • NF-κB
  • cell invasion in 3D culture
  • chemokine
  • fragment molecular orbital method
  • heparan sulfate degradation
  • heparanase
  • heparin
  • sulfated hyaluronan


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