The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes

He, Yi; Sutcliffe, Elissa L; Bunting, Karen; Li, Jasmine; Goodall, Katharine J.; Poon, Ivan K. H.; Hulett, Mark D.; Freeman, Craig; Zafar, Anjum; McInnes, Russell; Taya, Toshiki; Parish, Christopher R.; Rao, Sudha

doi:10.4161/trns.19998

Cited by 58 publications

(89 citation statements)

References 79 publications

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“…15 In addition to liberating HSPG-bound proteins, heparanase, either by binding to putative cell-surface receptors, or subsequent to its internalization and nuclear entry, has also been suggested to affect gene transcription. 5,[11][12][13][14]33,34 In cancer cells, this property of secreted heparanase can induce cell signalling and gene expression in both parent and adjacent cells, maintaining their survival and delaying demise. 11,16,17,[35][36][37] Our data suggest, for the first time, that HG promotes both the secretion of heparanase from EC as well as its uptake into cardiomyocytes, initiating prosurvival mechanisms to temper the consequences of hyperglycemia in the diabetic heart.…”

Section: Discussionmentioning

confidence: 99%

“…5,[7][8][9] Following its nuclear entry, Hep A also influences transcription by cleaving nuclear HSPG, mitigating the suppressive effect of heparan sulphate on histone acetyltransferase. [10][11][12][13][14] More recently, we established a novel role for Hep A in modulating cardiac metabolism during diabetes. 10,15 The above studies in cancer and diabetes fixated on the effects of Hep A , incorrectly assuming that only the HSPG-hydrolyzing ability of heparanase was of importance.…”

Section: In Cancer Biology Hepmentioning

confidence: 99%

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High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature

Wang

Jia

Lal

et al. 2016

Cardiovascular Research

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Aims The secretion of enzymatically active heparanase (HepA) has been implicated as an essential metabolic adaptation in the heart following diabetes. However, the regulation and function of the enzymatically inactive heparanase (HepL) remain poorly understood. We hypothesized that in response to high glucose (HG) and secretion of HepL from the endothelial cell (EC), HepL uptake and function can protect the cardiomyocyte by modifying its cell death signature. Methods and results HG promoted both HepL and HepA secretion from microvascular (rat heart micro vessel endothelial cells, RHMEC) and macrovascular (rat aortic endothelial cells, RAOEC) EC. However, only RAOEC were capable of HepL reuptake. This occurred through a low-density lipoprotein receptor-related protein 1 (LRP1) dependent mechanism, as LRP1 inhibition using small interfering RNA (siRNA), receptor-associated protein, or an LRP1 neutralizing antibody significantly reduced uptake. In cardiomyocytes, which have a negligible amount of heparanase gene expression, LRP1 also participated in the uptake of HepL. Exogenous addition of HepL to rat cardiomyocytes produced a dramatically altered expression of apoptosis-related genes, and protection against HG and H2O2 induced cell death. Cardiomyocytes from acutely diabetic rats demonstrated a robust increase in LRP1 expression and levels of heparanase, a pro-survival gene signature, and limited evidence of cell death, observations that were not apparent following chronic and progressive diabetes. Conclusion Our results highlight EC-to-cardiomyocyte transfer of heparanase to modulate the cardiomyocyte cell death signature. This mechanism was observed in the acutely diabetic heart, and its interruption following chronic diabetes may contribute towards the development of diabetic cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

Section: In Cancer Biology Hepmentioning

confidence: 99%

High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature

Wang

Jia

Lal

et al. 2016

Cardiovascular Research

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“…CXCL10 is therefore a new member in a growing list of genes regulated by heparanase and associated with tumorigenesis (i.e., VEGF, VEGF-C, TF, RANKL, HGF, MMP9). A novel set of genes under heparanase regulation has recently been characterized in T cells 41 . In this context, nuclear heparanase was shown to regulate the transcription of a cohort of inducible immune response genes by controlling histone H3 methylation 41 , further expanding the transcriptional potential of heparanase.…”

Section: Discussionmentioning

confidence: 99%

Heparanase enhances myeloma progression via CXCL10 downregulation

Barash¹,

Zohar²,

Wildbaum³

et al. 2014

Leukemia

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In order to explore the mechanism(s) underlying the pro-tumorigenic capacity of heparanase we established an inducible Tet-on system. Heparanase expression was markedly increased following addition of doxycycline (Dox) to the culture medium of CAG human myeloma cells infected with the inducible heparanase gene construct, resulting in increased colony number and size in soft agar. Moreover, tumor xenografts produced by CAG-heparanase cells were markedly increased in mice supplemented with Dox in their drinking water compared with control mice maintained without Dox. Consistently, we found that heparanase induction is associated with decreased levels of CXCL10, suggesting that this chemokine exerts tumor suppressor properties in myeloma. Indeed, recombinant CXCL10 attenuated the proliferation of CAG, U266 and RPMI-8266 myeloma cells. Similarly, CXCL10 attenuated the proliferation of human umbilical vein endothelial cells (HUVEC), implying that CXCL10 exhibits anti-angiogenic capacity. Strikingly, development of tumor xenografts produced by CAG-heparanase cells over expressing CXCL10 was markedly reduced compared with control cells. Moreover, tumor growth was significantly attenuated in mice inoculated with human or mouse myeloma cells and treated with CXCL10-Ig fusion protein, indicating that CXCL10 functions as a potent anti-myeloma cytokine.

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“…For example, pro-heparanase can induce cell signaling via PI3-kinase-mediated phosphorylation of AKT (38,39) and even act as a transcription factor regulating genes involved in cell differentiation, inflammation, and glucose metabolism (40)(41)(42). Other studies reported that heparanase enzymatic activity upregulates proinflammatory cytokines from human peripheral blood leukocytes (IL-1β, IL-6, IL-8, IL-10, and TNF), as well as mouse splenocytes (IL-6, MCP-1, and TNF) (43).…”

Section: Discussionmentioning

confidence: 99%

NK cell heparanase controls tumor invasion and immune surveillance

Putz

Mayfosh

Kos

et al. 2017

Journal of Clinical Investigation

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The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes

Abstract: (2012) The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes, Transcription,3:3,[130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145]

Cited by 58 publications

References 79 publications

High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature

High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature

Heparanase enhances myeloma progression via CXCL10 downregulation

NK cell heparanase controls tumor invasion and immune surveillance

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