Trans-activation of heparanase promoter by ETS transcription factors

Lu, Weiyue; Liu, Y N; Kang, Bean Bu; Chen, J H

doi:10.1038/sj.onc.1206201

Cited by 57 publications

(55 citation statements)

References 15 publications

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“…So far, the Sp1 and ETS families of transcription factors were studied and shown to participate and probably cooperate in the regulation of human heparanase expression. A greater influence was exerted by Sp1, GABP, ETS1 and ETS2 than by Sp3, PEA3 and ER81 (Jiang et al, 2002;Lu et al, 2003). Apparent inconsistency in the definition of a minimal promoter in these reports and the variable expression levels of mammalian heparanase suggest that this non-redundant gene is governed by a complex multifactorial mechanism.…”

Section: Discussionmentioning

confidence: 75%

“…Indeed, the gene is likely to be strictly controlled at multiple levels because of its uniqueness and due to the importance of heparanase function in mammalian cells. In fact, expression of the enzyme in different cell types has already been shown to be regulated by a variety of transcription factors (e.g., NFkB, Sp1 and ETS families) (Andela et al, 2000;Jiang et al, 2002;Lu et al, 2003), cytokines and hormones (e.g., estrogen, our unpublished results). Nevertheless, a general hypothetical model can plausibly incorporate the current evidence.…”

Section: Discussionmentioning

confidence: 99%

“…Two recent reports describe mutational and functional analysis of the human HPSE promoter in three tumour cell lines (Jiang et al, 2002;Lu et al, 2003). These studies identified a minimal basic promoter region of HPSE that spans 300-700 bp proximally to the ATG translation initiation site and contains binding sites for several groups of transcription factors.…”

Section: Discussionmentioning

confidence: 99%

“…However, the mechanisms responsible for heparanase overexpression in cancer remain largely unknown. Mutational and functional analysis emphasize the importance of two ETS binding sites near the 5 0 portion of the human HPSE promoter in transactivation and upregulation of heparanase expression (Lu et al, 2003). It was also suggested that the Sp1 and GABP transcription factors participate in a cooperative regulation of HPSE promoter activity (Jiang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Role of promoter methylation in regulation of the mammalian heparanase gene

et al. 2003

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Mammalian heparanase (endo-b-glucuronidase) degrades heparan sulfate proteoglycans and is an important modulator of the extracellular matrix and associated factors. The enzyme is preferentially expressed in neoplastic tissues and contributes to tumour metastasis and angiogenesis. To investigate the epigenetic regulation of the heparanase locus, methylation-specific and bisulfite PCR were performed on a panel of 22 human cancer cell lines. Cytosine methylation of the heparanase promoter was associated with inactivation of the affected allele. Despite lack of sequence homology, extensively methylated CpG islands were found both in human choriocarcinoma (JAR) and rat glioma (C-6) cells which lack heparanase activity. Treatment of these cells with demethylating agents (5-azacytidine, 5-aza-2 0 -deoxycytidine) resulted in stable dose-and time-dependant promoter hypomethylation accompanied by reappearance of heparanase mRNA, protein and enzymatic activity. An inhibitor of histone deacetylase, Trichostatin A, failed to induce either of these effects. Upregulation of heparanase expression and activity by demethylating drugs was associated with a marked increase in lung colonization by pretreated C-6 rat glioma cells. The increased metastatic potential in vivo was inhibited in mice treated with laminaran sulfate, a potent inhibitor of heparanase activity. We propose a model wherein expression of mammalian heparanase gene is modulated by the interplay between trans-activating genetic and cis-inhibitory epigenetic elements in its promoter.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of promoter methylation in regulation of the mammalian heparanase gene

et al. 2003

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“…Heparanase overexpression in multiple human tumors suggests a transcriptional regulation. Heparanase gene expression has been shown to involve promoter methylation, 38 eukaryotic initiation factor 4E, 39 and the ETS 40 and Egr1 41 transcription factors. Regulation at the post-translational level, namely heparanase processing, cellular localization and secretion, has also been implicated as major regulatory mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Doviner

Maly

Kaplan³

et al. 2006

Modern Pathology

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Heparanase is a mammalian endo-b-D-glucuronidase that cleaves heparan sulfate side chains at a limited number of sites. Such enzymatic activity is thought to participate in degradation and remodeling of the extracellular matrix and to facilitate cell invasion associated with tumor metastasis, angiogenesis and inflammation. Traditionally, heparanase activity was well correlated with the metastatic potential of a large number of tumor-derived cell types. More recently, heparanase upregulation has been documented in an increasing number of primary human tumors, correlating with poor postoperative survival and increased tumor vascularity. Here, we employed antiheparanase 733 polyclonal antibody that preferentially recognizes the 50 kDa active heparanase subunit over the 65 kDa proenzyme, as well as anti-heparanase 92.4 monoclonal antibody that recognizes both the latent and the active enzyme, to follow heparanase expression, processing and localization throughout the adenoma-carcinoma transition of the colon epithelium. Normal (nondysplastic) mucosa of the large bowel near epithelial neoplasms, as well as areas of mild dysplasia in adenomas, exhibited a strong reactivity with antibody 733 that became even stronger in foci of moderate dysplasia. Interestingly, although reactivity with antibody 733 was markedly reduced in severe dysplasia and in colorectal carcinoma, response to antibody 92.4 exhibited the opposite trend and staining intensities increased in parallel with tumor stage, the highest being in carcinoma cells. Involvement of latent heparanase (detected by 92.4, but not by 733 antibody) in tumor progression was suggested by activation of the Akt/PKB signal transduction pathway upon heparanase overexpression or exogenous addition to HT29 human colon carcinoma cells. These results suggest that heparanase expression is induced during colon carcinogenesis, and that its processing, conformation and localization are tightly regulated during the course of colon adenoma-carcinoma progression. Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains of heparan sulfate proteoglycans. 1,2 Heparan sulfate proteoglycans consist of a protein core to which several heparan sulfate side chains are covalently attached. These complex macromolecules are highly abundant in the extracellular matrix and are thought to play an important structural role, contributing to extracellular matrix integrity and insolubility. 3 In addition, heparan sulfate side chains can bind to a variety of biological mediators such as growth factors, cytokines and chemokines, 4,5 thus functioning as a readily available reservoir that can be liberated upon local or systemic cues. Moreover, heparan sulfate proteoglycans on the cell surface participates directly in signal-transduction cascades by potentiating the interaction between certain growth factors and their receptors. 6-9 Heparan sulfate-degrading activity is thus expected to affect several fundamental aspects of cell behavior under normal and clinical settings. 1,2 Tr...

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Heparanase 1 involvement in prostate physiopathology

Barbosa

Cervigne

Carvalho

et al. 2017

Cell Biology International

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The prostate is a compound exocrine gland of the male reproductive tract universally present in mammals. It is highly responsive to androgen and can be committed by a variety of pathological complications as prostatitis, benign, and malignant proliferative changes, which may be intensified by aging. Prostate intensively turnover its extracellular matrix (ECM) either at homeostasis or disease which includes a dynamically change of glycosaminoglycan composition during the life of an individual. Among the different enzymes playing a role in such changes, heparanase-1 is responsible for cleaving heparan sulfate (HS) at a limited number of sites, clearly involved in tissue remodeling. Its activity has been strongly implicated in cell invasion associated with cancer metastasis, a consequence of the structural modification that loosens the ECM barrier. In the present review we focuses in some aspects of the prostate physiology and diseases, particular prostate cancer, evidencing how the HPSE-1 activity encompasses the relationship of both processes.

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Trans-activation of heparanase promoter by ETS transcription factors

Cited by 57 publications

References 15 publications

Role of promoter methylation in regulation of the mammalian heparanase gene

Role of promoter methylation in regulation of the mammalian heparanase gene

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Heparanase 1 involvement in prostate physiopathology

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