Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity

Yang, Yi; Gorzelanny, Christian; Bauer, Alexander; Halter, Natalia; Komljenovic, Dorde; Bäuerle, Tobias; Borsig, Lubor; Roblek, Marko; Schneider, Stefan W.

doi:10.1038/onc.2015.40

Cited by 39 publications

(46 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A corresponding decrease in nuclear heparan sulfate further confirms this observation (Figure 4C). Bearing in mind previous suggestions of the ability of HPSE to localize to the nucleus (Schubert et al, 2004; Nobuhisa et al, 2007), bind to DNA (Yang et al, 2015), and regulate chromatin modifications (He et al, 2012; Hong et al, 2012), we hypothesized that HPSE influences cytokine signaling by interaction with transcription factors. Indeed, western blot analysis of nuclear and cytoplasmic extracts from HCE cells (Figure 4D,E) and HeLa cells (Figure S3D) overexpressing GS3-HPSE showed significantly enhanced translocation of nuclear factor (NF)-κB to the nucleus upon infection.…”

Section: Resultsmentioning

confidence: 99%

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

et al. 2017

View full text Add to dashboard Cite

Summary Herpes simplex virus type-1 (HSV-1) causes lifelong recurrent pathologies without a cure. How infection by HSV-1 triggers disease processes, especially in the immune-privileged avascular human cornea, remains a major unresolved puzzle. It has been speculated that a cornea-resident molecule must tip the balance in favor of pro-inflammatory and pro-angiogenic conditions observed with herpetic as well as non-herpetic ailments of the cornea. Here, we demonstrate that heparanase (HPSE), a host enzyme, is the molecular trigger for multiple pathologies associated with HSV-1 infection. In human corneal epithelial cells, HSV-1 infection upregulates HPSE in a manner dependent on HSV-1 infected cell protein 34.5. HPSE then relocates to the nucleus to regulate cytokine production, inhibits wound closure, enhances viral spread, and thus generates a toxic local environment. Overall, our findings implicate activated HPSE as a driver of viral pathogenesis, and call for further attention to this host protein in infection and other inflammatory disorders.

show abstract

Section: Resultsmentioning

confidence: 99%

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Heparanase can also interfere with gene transcription directly by binding to nuclear DNA or indirectly by controlling histone H3 methylation patterns . The overexpression of heparanase in melanoma cell lines prompted us to study its role on cancer cells per se . Accordingly, melanoma MDA‐MB‐435s cells and MV3 cells expressed remarkably high levels of endogenous heparanase (Figure A).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis reveals cell apoptotic signature modified by heparanase in melanoma cells

Song

Spillmann

2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

Heparanase has been implicated in many pathological conditions, especially inflammation and cancer, attributed to its degradation of heparan sulfate, a crucial component maintaining the integrity of the extracellular matrix. By silencing the heparanase gene (HPSE) in MDA‐MB‐435s melanoma cells, we investigated the impact of this protein on gene transcription. Transcriptome sequencing yielded a list of 279 differentially expressed genes, of which 140 were up‐regulated and 239 down‐regulated. The 140 up‐regulated genes were classified into a substantial set of gene ontology defined functions, for example, positive regulation of cell death, apoptotic process, response to cytokine, while 239 down‐regulated genes classify only into the two categories: nucleosome and nucleosome assembly. Our focus was drawn to an array of 28 pro‐apoptotic genes regulated by heparanase: real‐time PCR experiments further validated up‐regulation of EGR1, TXNIP, AXL, CYR61, LIMS2 and TNFRSF12A by at least 1.5‐fold, among which EGR1, CYR61, and TNFRSF12A were confirmed on protein level. We demonstrated significantly increased apoptotic cells by TUNEL staining upon HPSE silencing, mediated by activation of caspase 3/PARP1 pathway. The pro‐apoptotic gene expression and observation of apoptosis were extended to another melanoma cell line, MV3 cells, thus consolidating the anti‐apoptosis effect of heparanase in melanoma cells.

show abstract

“…HS is a glycosaminoglycan (GAG) that is present in almost all mammalian tissues on cell surfaces and in the extracellular matrix (17,26,27). It plays a key role in ECM integrity, barrier function, and cell-ECM interactions and is used by many viruses for initial attachment to target cells.…”

Section: Discussionmentioning

confidence: 99%

“…HS is present in almost all mammalian tissues and plays a key role in ECM integrity, barrier function, and cell-ECM interactions (16). As the only known enzyme capable of degrading HS at specific intrachain sites, heparanase (HPSE) mediates the release of HS-bound cytokines, growth factors, lipoproteins, enzymes, and viruses (17). Previous studies have shown that HS expression is increased during the initial stage of herpes simplex virus 1 (HSV-1) infection to enhance viral attachment to cells.…”

mentioning

confidence: 99%

Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release

Guo

Zhu

Guo

et al. 2017

J Virol

View full text Add to dashboard Cite

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Heparan sulfate (HS) is used by PRRSV for initial attachment to target cells. However, the role of HS in the late phase of PRRSV infection and the mechanism of virus release from host cells remain largely unknown. In this study, we showed that PRRSV infection caused a decrease in HS expression and upregulated heparanase, the only known enzyme capable of degrading HS. We subsequently demonstrated that the NF-B signaling pathway and cathepsin L protease were involved in regulation of PRRSV infectioninduced heparanase. In addition, we found that ablation of heparanase expression using small interfering RNA duplexes increased cell surface expression of HS and suppressed PRRSV replication and release, whereas overexpression of heparanase reduced HS surface expression and enhanced PRRSV replication and release. These data suggest that PRRSV activates NF-B and cathepsin L to upregulate and process heparanase, and then the active heparanase cleaves HS, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) causes great economic losses each year to the pig industry worldwide. The molecular mechanism of PRRSV release from host cells largely remains a mystery. In this study, we demonstrate that PRRSV activates NF-B and cathepsin L to upregulate and process heparanase, and then the active heparanase is released to the extracellular space and exerts enzymatic activity to cleave heparan sulfate, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.KEYWORDS PRRSV, heparan sulfate, heparanase, viral release, porcine reproductive and respiratory syndrome virus P orcine reproductive and respiratory syndrome (PRRS) has become one of the most important diseases of intensive pig production worldwide since its emergence in the late 1980s (1, 2). This disease is characterized by respiratory disease, weight loss, and poor growth performance, as well as by late-term abortions (3). The causative agent, PRRS virus (PRRSV), is a small, enveloped, positive-sense, single-stranded RNA virus of the genus Arterivirus, in the family Arteriviridae within the order Nidovirales (4, 5). The PRRSV genome is approximately 15 kb in length and consists of at least 12 overlapping open reading frames (6, 7). Due to the genetic and antigenic differences, PRRSV can be divided into European genotype 1 and North American genotype 2, with Lelystad and VR-2332 as prototypical strains, respectively, which share about 60% nucleotide sequence identity (8). In 2006, highly pathogenic PRRSV (HP-PRRSV)

show abstract

Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity

Cited by 39 publications

References 58 publications

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

Transcriptomic analysis reveals cell apoptotic signature modified by heparanase in melanoma cells

Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release

Contact Info

Product

Resources

About