Role of promoter methylation in regulation of the mammalian heparanase gene

Shteper, Pesach J; Zcharia, Eyal; Ashhab, Yaqoub; Peretz, Tamar; Vlodavsky, Israël; Ben‐Yehuda, Dina

doi:10.1038/sj.onc.1207056

Cited by 97 publications

(90 citation statements)

References 68 publications

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“…This is best demonstrated in Raji cells that lack intrinsic heparanase activity ( Fig. 1E) (20), whereas tumor xenografts produced by these cells exhibit typical heparanase activity. The ability of mAbs 9E8 and H1023 to attenuate the growth of these tumors (Figs.…”

Section: Discussionmentioning

confidence: 93%

“…Despite the lack of heparanase activity in Raji cells (Fig. 1E, Upper, Raji cells) because of gene methylation (20), tumor xenografts produced by Raji cells exhibit typical heparanase activity (Fig. 1E, Upper, Raji tumor), suggesting that heparanase-positive cells derived from the host populate the tumor microenvironment.…”

Section: Inhibition Of Heparanase Originating From the Tumor Microenvmentioning

confidence: 99%

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Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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104

140

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Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanaseneutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment.heparanase | lymphoma | neutralizing antibody | tumor growth | metastasis H eparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, releasing saccharide products with appreciable size (4-7 kDa) and biological potency. Enzymatic degradation of HS leads to disassembly of the extracellular matrix (ECM) and correlates with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM and basement membrane underlying epithelial and endothelial cells (1, 2). Heparanase expression is induced in human cancer, most often associating with reduced patients' survival postoperation, increased tumor metastasis, and higher vessel density (3-5). In addition, heparanase up-regulation is associated with tumors larger in size (3, 5). Likewise, heparanase over-expression enhanced (6, 7), whereas local delivery of anti-heparanase siRNA inhibited (8), the growth of tumor xenografts. These results imply that heparanase function is not limited to tumor metastasis but is engaged in progression of the primary lesion, thus critically supporting the intimate involvement of heparanase in tumor progression and encouraging the development of heparanase inhibitors as anticancer therapeutics (9-12). As a consequence, heparanase inhibitors are currently evaluated in phase 1 clinical trials (13).Heparanase activity is similarly implicated in the progression of multiple myeloma (14-16), but its significan...

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Section: Discussionmentioning

confidence: 93%

Section: Inhibition Of Heparanase Originating From the Tumor Microenvmentioning

confidence: 99%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

140

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“…Heparanase expression in bladder cancer T Ogishima et al treatment, suggesting that promoter methylation could be involved in the transcriptional regulation of the heparanase gene (Shteper et al, 2003). Based on the functional promoter sequence of heparanase gene (De Mestre et al, 2003), MSP and USP primers were specifically designed to analyse the difference in promoter CpG methylation between normal bladder and bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Also, the prevalence of genome-wide hypomethylation has been described in several cancers (Kaneda et al, 2004) and site-specific hypomethylation of the promoter region has been shown to upregulate the expression of cancer-promoting genes (Ehrlich, 2002). Recently, promoter methylation has been associated with the regulation of heparanase expression in cancer cell lines (Shteper et al, 2003). In addition to the active involvement of promoter methylation in heparanase regulation, early growth response 1 (EGR1), a member of the zinc-finger family of transcription factors, has been shown to be important in the inducible transcription of the heparanase gene (De Mestre et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer

et al. 2005

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Heparanase plays a critical role in the degradation of extracellular matrix and cell membrane and is frequently upregulated in malignant tumors. Transcription factor, early growth response 1 (EGR1), is closely associated with inducible transcription of the heparanase gene. We hypothesized that promoter CpG hypomethylation with increased EGR1 expression could determine heparanase expression during the pathogenesis of bladder cancer. Bladder cancer cell lines (J82, T24 and transitional cell carcinoma) significantly restored heparanase expression after 5-AzadC treatment. Transfection of EGR1 siRNA with T24 bladder cancer cell line significantly downregulated heparanase expression compared to the control siRNA transfection. In 54 bladder cancer and paired normal bladder samples, heparanase expression was significantly higher in bladder cancer than in normal bladder (Po0.01). We performed methylation-specific PCR targeting the CpG sites within the core-binding consensus motifs of EGR1 (GGCG) and Sp1 (GGGCGG). Methylation prevalence was significantly higher in normal bladder than in bladder cancer (Po0.05) and inversely correlated with heparanase expression (P ¼ 0.055). In the total series of bladder cancer and normal bladder samples, the combination of promoter CpG methylation and EGR1 expression regulated heparanase expression in a stepwise manner, where heparanase expression was the lowest in methylation-positive and EGR1-negative samples and the highest in methylation-negative and EGR1-positive samples. To our knowledge, this is the first study demonstrating that increased heparanase expression during the pathogenesis of bladder cancer is due to promoter hypomethylation and transcription factor EGR1.

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“…Induced heparanase expression under pathological conditions suggests a transcriptional regulation. Heparanase gene expression has been shown to involve promoter methylation (22), eukaryotic initiation factor 4E (23), and the Ets (24) and Egr1 (25) transcription factors. Recently, estrogen has been shown to induce heparanase promoter activation in estrogen receptor-positive breast cancer cells (26).…”

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confidence: 99%

Heparanase Uptake Is Mediated by Cell Membrane Heparan Sulfate Proteoglycans

Gingis-Velitski¹,

Zetser²,

Kaplan³

et al. 2004

Journal of Biological Chemistry

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211

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Heparanase is a mammalian endoglycosidase that degrades heparan sulfate (HS) at specific intrachain sites, an activity that is strongly implicated in cell dissemination associated with metastasis and inflammation. In addition to its structural role in extracellular matrix assembly and integrity, HS sequesters a multitude of polypeptides that reside in the extracellular matrix as a reservoir. A variety of growth factors, cytokines, chemokines, and enzymes can be released by heparanase activity and profoundly affect cell and tissue function. Thus, heparanase bioavailability, accessibility, and activity should be kept tightly regulated. We provide evidence that HS is not only a substrate for, but also a regulator of, heparanase. Addition of heparin or xylosides to cell cultures resulted in a pronounced accumulation of, heparanase in the culture medium, whereas sodium chlorate had no such effect. Moreover, cellular uptake of heparanase was markedly reduced in HS-deficient CHO-745 mutant cells, heparan sulfate proteoglycan-deficient HT-29 colon cancer cells, and heparinasetreated cells. We also studied the heparanase biosynthetic route and found that the half-life of the active enzyme is ϳ30 h. This and previous localization studies suggest that heparanase resides in the endosomal/lysosomal compartment for a relatively long period of time and is likely to play a role in the normal turnover of HS. Co-localization studies and cell fractionation following heparanase addition have identified syndecan family members as candidate molecules responsible for heparanase uptake, providing an efficient mechanism that limits extracellular accumulation and function of heparanase.

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Role of promoter methylation in regulation of the mammalian heparanase gene

Cited by 97 publications

References 68 publications

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer

Heparanase Uptake Is Mediated by Cell Membrane Heparan Sulfate Proteoglycans

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