Extracellular endosulfatase Sulf-2 harbors a chondroitin/dermatan sulfate chain that modulates its enzyme activity

Masri, Rana El; Seffouh, Amal; Roelants, Caroline; Seffouh, Ilham; Gout, Evelyne; Pérard, Julien; Dalonneau, Fabien; Nishitsuji, Kazuchika; Noborn, Fredrik; Nikpour, Mahnaz; Larson, Göran; Crétinon, Yoann; Friedel-Arboleas, Mélanie; Uchimura, Kenji; Daniel, Régis; Lortat‐Jacob, Hugues; Filhol, Odile; Vivès, Romain R.

doi:10.1016/j.celrep.2022.110516

Cited by 17 publications

(10 citation statements)

References 45 publications

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“…We therefore tested the ability of a fucosylated chondroitin sulfate GAG isolated from the sea cucumber species H. floridana named as HfFucCS [34], to inhibit Sulf-2 and cancer cell invasion. We do this because a recent study has shown that a chondroitin sulfate modification negatively regulates the activity of the Sulf-2 enzyme [54], marine organisms are a rich natural source of unique GAG polymers [55], and efficient inhibitors of the Sulf-2 enzyme are not available. Several compounds were tested as Sulf-2 inhibitors [56][57][58] but they are either inefficient or not available.…”

Section: Discussionmentioning

confidence: 99%

Heparan-6-O-endosulfatase 2 promotes invasiveness of head and neck squamous carcinoma cell lines in co-cultures with cancer associated fibroblasts

Mukherjee,

Zhou,

Benicky

et al. 2023

Preprint

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Local invasiveness of head and neck squamous cell carcinoma (HNSCC) is a complex phenomenon supported by interaction of the cancer cells with the TME. We and others have shown that CAFs are a component of the TME that can promote local invasion in HNSCC and other cancers. Here we report that the secretory enzyme Sulf-2 directly affects the CAF-supported invasion of HNSCC cell lines SCC35 and Cal33 into Matrigel. The Sulf-2 knockout (KO) cells differ from their wild type counterparts in their spheroid growths and formation, and the Sulf-2-KO leads to decreased invasion in a spheroid co-culture model with the CAF. Next, we investigated whether a fucosylated chondroitin sulfate isolated from the sea cucumberHolothuria Floridana(HfFucCS), affects activity of the Sulf-2 enzyme. Our results show that HfFucCS not only inhibits efficiently the Sulf-2 enzymatic activity but, like the Sulf-2 knockout, inhibits Matrigel invasion of the SCC35 and Cal33 cells co-cultured with the primary HNSCC CAF. These findings suggest that the heparan 6-O-endosulfatases regulate local invasion and could be therapeutically targeted with the inhibitory activity of a marine glycosaminoglycan.Simple SummaryLocal invasion of cancer cells is an early step in the cascade of metastasis that requires cooperation of multiple factors and cell types in the tumor microenvironment (TME). One important factor is the crosstalk of cancer cells with cancer associated fibroblasts (CAF). Here we explore the impact of a secretory enzyme heparan-6-O-endosulfatase 2 (Sulf-2) on the CAF-assisted invasion of head and neck squamous carcinoma cells into matrigel. We show that Sulf-2 knock out inhibits cancer cell invasion in a spheroid co-culture model and we identified a novel Sulf-2 inhibitor that, in the same model, limits cancer cell invasion.

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Section: Discussionmentioning

confidence: 99%

Heparan-6-O-endosulfatase 2 promotes invasiveness of head and neck squamous carcinoma cell lines in co-cultures with cancer associated fibroblasts

Mukherjee,

Zhou,

Benicky

et al. 2023

Preprint

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“…We have strong evidence that SULF1 is supplied by CAF while SULF2 is provided primarily by the cancer cells, which has important consequences because the secreted SULF enzymes act locally due to strong non-covalent interactions with cell surfaces [ 7 ]. In addition, recent data suggest that their activity is regulated by cell-specific posttranslational modifications [ 46 ]. We know that SULFs regulate oncogenic pathways but they also adjust matrix structure, angiogenesis, or immune responses [ 3 , 4 , 7 , 8 , 10 , 15 , 16 , 17 , 47 , 48 ], and their function at the tumor/stroma interface in different cancers needs further study.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Heparan 6-O-Endosulfatases SULF1 and SULF2 in Head and Neck Squamous Cell Carcinoma and Other Malignancies

Yang

Ahn

Edwards

et al. 2022

Cancers

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Pan-cancer analysis of TCGA and CPTAC (proteomics) data shows that SULF1 and SULF2 are oncogenic in a number of human malignancies and associated with poor survival outcomes. Our studies document a consistent upregulation of SULF1 and SULF2 in HNSC which is associated with poor survival outcomes. These heparan sulfate editing enzymes were considered largely functional redundant but single-cell RNAseq (scRNAseq) shows that SULF1 is secreted by cancer-associated fibroblasts in contrast to the SULF2 derived from tumor cells. Our RNAScope and patient-derived xenograft (PDX) analysis of the HNSC tissues fully confirm the stromal source of SULF1 and explain the uniform impact of this enzyme on the biology of multiple malignancies. In summary, SULF2 expression increases in multiple malignancies but less consistently than SULF1, which uniformly increases in the tumor tissues and negatively impacts survival in several types of cancer even though its expression in cancer cells is low. This paradigm is common to multiple malignancies and suggests a potential for diagnostic and therapeutic targeting of the heparan sulfatases in cancer diseases.

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“…Both cell-associated [58][59][60] and secreted [31,56,59] forms of SULF2 have been described, suggesting the enzyme can act in both an autocrine and paracrine manner. Recently, El Masri et al [61] found that SULF2 localisation and activity can be modulated by post-translational modification, with attachment of a chondroitin or dermatan sulfate glycosaminoglycan chain to the enzyme's HD domain increasing cell surface association and reducing 6-O-sulfatase activity. Degradation of the glycosaminoglycan chain by hyaluronidase reduced cell surface binding and increased SULF2 activity [61].…”

Section: Increased Type I Interferon Signaling In Sulf2-deficient Mac...mentioning

confidence: 99%

The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis

Swart,

Redpath,

Ogbechi

et al. 2024

Preprint

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Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene wasSulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generatedSulf2+/-bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloidSulf2+/-chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic andin vitroanalyses indicated thatSulf2deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL-6. This establishes that dynamic remodeling of HS bySulf2limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology.

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Extracellular endosulfatase Sulf-2 harbors a chondroitin/dermatan sulfate chain that modulates its enzyme activity

Cited by 17 publications

References 45 publications

Heparan-6-O-endosulfatase 2 promotes invasiveness of head and neck squamous carcinoma cell lines in co-cultures with cancer associated fibroblasts

Heparan-6-O-endosulfatase 2 promotes invasiveness of head and neck squamous carcinoma cell lines in co-cultures with cancer associated fibroblasts

Extracellular Heparan 6-O-Endosulfatases SULF1 and SULF2 in Head and Neck Squamous Cell Carcinoma and Other Malignancies

The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis

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