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In this study we investigated epigenetic modifications such as DNA methylation,histone acetylation and histone methylation in the regulation of heparanase expressionin glioblastoma. We found that heparanase promoters are differentially methylatedamong three glioblastoma cell lines; however, all these cells expressed baselinelevels of heparanase. 5-Aza-2'-deoxycytidine (5-Aza-dC), a DNA methyltransferaseinhibitor, revoked heparanase expression in all the examined cells. TrichostatinA (TSA), a histone deacetylase inhibitor, activated heparanase expression in promoterunmethylated LN229 and T98G cells but not in promoter methylated U251n cells.To identify the mechanisms of heparanase induction by 5-Aza-dC, heparanase expression-relatedtranscription factors were examined. No detected transcription factors (EGR1,Ets1, GABPα and Sp1) were found to be induced either by 5-Aza-dC or TSA. Furthermore,we found that 5-Aza-dC increased acetylation of histone H3 and di-methylationof histone H3 lysine K4 (H3K4me2) in LN229 and T98G cells. The increased histoneacetylation and H3K4me2 were also observed in heparanase-expressing tumor tissuesby immunohistochemistry staining. Additionally, we found that nuclear factor κB(NFκB) p65 but not NFκB p50 was correlated with heparanase expression, which couldbe expressed both by neoplastic cells and angiogenesis-related neovessel cells.However, we did not observe any regulatory mechanism between heparanase and NFκBp65 via transient transfection of their cDNA in T98G and U251n cells. We concludedthat heparanase expression is associated with histone modifications and promoterDNA methylation plays a role in the control of gene silencing. Overexpressionof both heparanase and NFκB p65 may be the result of excessive histone modifications.

Heparanase expression is associated with histone modifications in glioblastoma