Heparanase: Cloning, Function and Regulation

Gaskin, Shaun M; Costa, Tatiana P. Soares da; Hulett, Mark D.

doi:10.1007/978-3-030-34521-1_7

Cited by 10 publications

(16 citation statements)

References 213 publications

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“…[27][28][29][30][31][32][33][34] Heparanase Heparanase is the sole heparan sulfate degrading endoglycosidase present in mammals. [35][36][37][38] Human heparanase mRNA encodes for a 61.2-kDa protein containing 543 amino acids. This proenzyme form is then cleaved by cathepsin L to generate the active form consisting of 8 and 50 kDa subunits that associate noncovalently.…”

Section: Glycocalyxmentioning

confidence: 99%

“…84 Nuclear heparan sulfate chains in conjunction with heparanase can influence numerous events, including the promotion of mitotic spindle formation and subsequent chromosome stability, inhibition of DNA topoisomerase-I activity, and regulation of cell proliferation. 35,80,[85][86][87][88][89][90] The majority of the nuclear shed syndecan-1 was observed in discrete patches within the euchromatin, the area of active gene transcription. Moreover, it was found that shed syndecan-1 in the nucleus of bone marrow-derived stromal cells binds to the histone acetyltransferase (HAT) enzyme via HS chains and diminishes HAT activity and histone H3 acetylation.…”

Section: Shed Syndecan-1 In the Nucleusmentioning

confidence: 99%

“…Thus, the stimulatory effect that heparanase has on exosome biogenesis is related to its ability to enzymatically alter the heparan sulfate chains of syndecan, thereby facilitating intraluminal budding and formation of exosomes. 35,98,99 Mechanistically, heparanase enhances exosome biogenesis by stimulating endocytosis of syndecans and by acting through the syntenin-Alix pathway to stimulate shortening the heparan sulfate chains of syndecan-1 and thereby intraluminal budding of vesicles. 99 Analysis of exosome cargo secreted by myeloma cells expressing heparanase at a high level revealed more syndecan-1, VEGF, HGF, and fibronectin than was present in exosomes secreted by cells expressing at low level of heparanase.…”

Section: Exosomesmentioning

confidence: 99%

See 2 more Smart Citations

Biology of the Heparanase–Heparan Sulfate Axis and Its Role in Disease Pathogenesis

Vlodavsky

Barash

Nguyen

et al. 2021

Semin Thromb Hemost

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Cell surface proteoglycans are important constituents of the glycocalyx and participate in cell–cell and cell–extracellular matrix (ECM) interactions, enzyme activation and inhibition, and multiple signaling routes, thereby regulating cell proliferation, survival, adhesion, migration, and differentiation. Heparanase, the sole mammalian heparan sulfate degrading endoglycosidase, acts as an “activator” of HS proteoglycans, thus regulating tissue hemostasis. Heparanase is a multifaceted enzyme that together with heparan sulfate, primarily syndecan-1, drives signal transduction, immune cell activation, exosome formation, autophagy, and gene transcription via enzymatic and nonenzymatic activities. An important feature is the ability of heparanase to stimulate syndecan-1 shedding, thereby impacting cell behavior both locally and distally from its cell of origin. Heparanase releases a myriad of HS-bound growth factors, cytokines, and chemokines that are sequestered by heparan sulfate in the glycocalyx and ECM. Collectively, the heparan sulfate–heparanase axis plays pivotal roles in creating a permissive environment for cell proliferation, differentiation, and function, often resulting in the pathogenesis of diseases such as cancer, inflammation, endotheliitis, kidney dysfunction, tissue fibrosis, and viral infection.

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Section: Glycocalyxmentioning

confidence: 99%

Section: Shed Syndecan-1 In the Nucleusmentioning

confidence: 99%

Section: Exosomesmentioning

confidence: 99%

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Biology of the Heparanase–Heparan Sulfate Axis and Its Role in Disease Pathogenesis

Vlodavsky

Barash

Nguyen

et al. 2021

Semin Thromb Hemost

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“…Mammalian cells express a single dominant functional heparanase (HPSE) that cleaves heparan sulfate (HS), contributes to disassembly of the extracellular matrix, releases HSbound effector molecules, and thereby facilitates cancer metastasis and inflammation [1][2][3][4][5][6]. While human tissues reveal low expression of heparanase [5][6][7], constitutive or inducible heparanase expression was found in all hematopoietic cells, including neutrophils, activated lymphocytes, monocytes, macrophages, platelets, NK cells, mast cells, eosinophils, and dendritic cells [8][9][10]. A key role of heparanase in the function of the immune system has been identified [10].…”

Section: Introductionmentioning

confidence: 99%

“…While human tissues reveal low expression of heparanase [5][6][7], constitutive or inducible heparanase expression was found in all hematopoietic cells, including neutrophils, activated lymphocytes, monocytes, macrophages, platelets, NK cells, mast cells, eosinophils, and dendritic cells [8][9][10]. A key role of heparanase in the function of the immune system has been identified [10].…”

Section: Introductionmentioning

confidence: 99%

The HPSE Gene Insulator—A Novel Regulatory Element That Affects Heparanase Expression, Stem Cell Mobilization, and the Risk of Acute Graft versus Host Disease

Ostrovsky

Baryakh

Morgulis

et al. 2021

Cells

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The HPSE gene encodes heparanase (HPSE), a key player in cancer, inflammation, and autoimmunity. We have previously identified a strong HPSE gene enhancer involved in self-regulation of heparanase by negative feedback exerted in a functional rs4693608 single-nucleotide polymorphism (SNP) dependent manner. In the present study, we analyzed the HPSE gene insulator region, located in intron 9 and containing rs4426765, rs28649799, and rs4364254 SNPs. Our results indicate that this region exhibits HPSE regulatory activity. SNP substitutions lead to modulation of a unique DNA-protein complex that affects insulator activity. Analysis of interactions between enhancer and insulator SNPs revealed that rs4693608 has a major effect on HPSE expression and the risk of post-transplantation acute graft versus host disease (GVHD). The C alleles of insulator SNPs rs4364254 and rs4426765 modify the activity of the HPSE enhancer, resulting in altered HPSE expression and increased risk of acute GVHD. Moreover, rs4426765 correlated with HPSE expression in activated mononuclear cells, as well as with CD3 levels and lymphocyte counts following G-CSF mobilization. rs4363084 and rs28649799 were found to be associated with CD34+ levels. Our study provides new insight into the mechanism of HPSE gene regulation and its impact on normal and pathological processes in the hematopoietic system.

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Potential roles of heparanase in cancer therapy: Current trends and future direction

Yang

Yuan

Zhou

et al. 2023

Journal Cellular Physiology

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Heparanase (HPSE; heparanase‐1) is an endo‐β‐glucuronidase capable of degrading the carbohydrate moiety of heparan sulfate proteoglycans, thus modulating and facilitating the remodeling of the extracellular matrix and basement membrane. HPSE activity is strongly associated with major human pathological complications, including but not limited to tumor progress and angiogenesis. Several lines of literature have shown that overexpression of HPSE leads to enhanced tumor growth and metastatic transmission, as well as poor prognosis. Gene silencing of HPSE or treatment of tumor with compounds that block HPSE activity are shown to remarkably attenuate tumor progression. Therefore, targeting HPSE is considered as a potential therapeutical strategy for the treatment of cancer. Intriguingly, recent findings disclose that heparanase‐2 (HPSE‐2), a close homolog of HPSE but lacking enzymatic activity, can also regulate antitumor mechanisms. Given the pleiotropic roles of HPSE, further investigation is in demand to determine the precise mechanism of regulating action of HPSE in different cancer settings. In this review, we first summarize the current understanding of HPSE, such as its structure, subcellular localization, and tissue distribution. Furthermore, we systematically review the pro‐ and antitumorigenic roles and mechanisms of HPSE in cancer progress. In addition, we delineate HPSE inhibitors that have entered clinical trials and their therapeutic potential.

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Heparanase: Cloning, Function and Regulation

Cited by 10 publications

References 213 publications

Biology of the Heparanase–Heparan Sulfate Axis and Its Role in Disease Pathogenesis

Biology of the Heparanase–Heparan Sulfate Axis and Its Role in Disease Pathogenesis

The HPSE Gene Insulator—A Novel Regulatory Element That Affects Heparanase Expression, Stem Cell Mobilization, and the Risk of Acute Graft versus Host Disease

Potential roles of heparanase in cancer therapy: Current trends and future direction

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