Abstract
Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where it may function in regulating gene transcription. Using myeloma cell lines, we report here that heparanase enhances chromatin accessibility and confirm a previous report that it also upregulates the acetylation of histones. Employing the Multiple Myeloma Research Foundation CoMMpass database, we demonstrate that patients expressing high levels of heparanase display elevated expression of proteins involved in chromatin remodeling and several oncogenic factors compared to patients expressing low levels of heparanase. These signatures were consistent with the known function of heparanase in driving tumor progression. Chromatin opening and downstream target genes were abrogated by inhibition of heparanase. Enhanced levels of heparanase in myeloma cells led to a dramatic increase in phosphorylation of PTEN, an event known to stabilize PTEN, leading to its inactivity and loss of tumor suppressor function. Collectively, this study demonstrates that heparanase promotes chromatin opening and transcriptional activity, some of which likely is through its impact on diminishing PTEN tumor suppressor activity.
Highlights
Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate, thereby regulating the activity of growth factors, shedding of heparan sulfate proteoglycans and degradation of extracellular matrix that together promote cell invasion, metastasis and angiogenesis by [1]
The presence of heparanase in the nucleus leads to loss of the heparan sulfate proteoglycan syndecan-1 from the nucleus, resulting in enhanced histone acetyltransferase (HAT) activity and upregulation of expression of VEGF and matrix metalloproteinase-9 (MMP9), two genes that contribute to an aggressive tumor phenotype [6,7]
In the present study, using myeloma cell lines we find that: (i) within the nucleus, heparanase is present in the soluble fraction, and it is bound to insoluble chromatin; (ii) the presence of nuclear heparanase enhances acetylation of histone H3 and promotes an open chromatin conformation; (iii) heparanase binds the promoter region of syndecan-1, MMP9 and CCND1, three genes whose expression is upregulated by heparinase; and (iv) heparanase increases phosphorylation of PTEN, leading to enhanced PTEN stability thereby diminishing its function as a tumor suppressor
Summary
Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate, thereby regulating the activity of growth factors, shedding of heparan sulfate proteoglycans and degradation of extracellular matrix that together promote cell invasion, metastasis and angiogenesis by [1]. Heparanase is present in different subcellular locations, including within the extracellular matrix, at the cell surface and intracellularly within the cytoplasm [1]. Active heparanase capable of degrading heparan sulfate is present within the nucleus and was first reported in glioma and breast cancer cells [4]. The presence of heparanase in the nucleus leads to loss of the heparan sulfate proteoglycan syndecan-1 from the nucleus, resulting in enhanced histone acetyltransferase (HAT) activity and upregulation of expression of VEGF and MMP9, two genes that contribute to an aggressive tumor phenotype [6,7]
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