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Abstract
Heparanase is an endo-β-glucuronidase that specifically cleaves the saccharide chains of heparan sulfate (HS) proteoglycans and releases HS-bound cytokines, chemokines, and bioactive growth-promoting factors. Heparanase plays an important role in the nucleus as part of an active chromatin complex. Our previous studies revealed that rs4693608 correlates with heparanase levels and increased risk of acute and extensive chronic graft vs. host disease (GVHD). Discrepancy between recipient and donor in this SNP significantly affected the risk of acute GVHD. In the present study, we analyzed the HPSE gene region, including rs4693608, and demonstrated that this region exhibits SNPs-dependent enhancer activity. Analysis of nuclear proteins from normal leukocytes revealed their binding to DNA probe of both alleles with higher affinity to allele G. All malignant cell lines and leukemia samples disclosed a shift of the main bands in comparison to normal leukocytes. At least five additional shifted bands were bound to allele A while allele G probe was bound to only one main DNA/protein complex. Additional SNPs rs4693083, rs4693084, and rs4693609 were found in strong linkage disequilibrium (LD) with rs11099592 (exon 7). Only rs4693084 affected protein binding to DNA in cell lines and leukemia samples. As a result of the short distance between rs4693608 and rs4693084, both SNPs may be included in a common DNA/protein complex. DNA pull-down assay revealed that heparanase is involved in self-regulation by negative feedback in rs4693608-dependent manner. During carcinogenesis, heparanase self-regulation is discontinued and the helicase-like transcription factor begins to regulate this enhancer region. Altogether, our study elucidates conceivable mechanism(s) by which rs4693608 SNP regulates HPSE gene expression and the associated disease outcome.
Highlights
Heparanase is an endo-β-glucuronidase that cleaves the saccharide chains of heparan sulfate (HS)(ECM)
The SNP genotype frequencies did not significantly deviate from the Hardy–Weinberg distribution. rs4693083, rs4693084, and rs4693609 were found in strong linkage disequilibrium (LD)
Genetic variations contribute to disease development by alterations in transcription factor binding, enhancer activity, long-range enhancer–promoter interactions, posttranslational histone modifications, and/or RNA polymerase function
Summary
Heparanase is an endo-β-glucuronidase that cleaves the saccharide chains of heparan sulfate (HS)(ECM). Cleavage of HS by active heparanase leads to loss of integrity of the basement membrane and ECM and release of HS-bound cytokines, chemokines, and growthpromoting factors[1,2,3,4,5,6]. Heparanase plays critical roles in tumor metastasis and angiogenesis[5]. High expression of heparanase is Ostrovsky et al Oncogenesis (2018)7:51 frequently observed in an increasing number of primary human tumors of all etiologies (carcinoma, sarcoma, and hematological malignancies), correlating with high vessel density and poor clinical outcome[7,8,9,10]. Heparanase plays a role in the nucleus as part of an active chromatin complex which regulates inducible gene transcription. Nuclear heparanase associates with euchromatin and regulates histone H3K4 and H3K9 methylation by binding to target gene regulatory regions in association with the demethylase LSD116
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