Heparanase expression is associated with histone modifications in glioblastoma

Abstract

Abstract. In this study we investigated epigenetic modifications such as DNA methylation, histone acetylation and histone methylation in the regulation of heparanase expression in glioblastoma. We found that heparanase promoters are differentially methylated among three glioblastoma cell lines; however, all these cells expressed baseline levels of heparanase. 5-Aza-2'-deoxycytidine (5-Aza-dC), a DNA methyltransferase inhibitor, revoked heparanase expression in all the examined cells. Trichostatin A (TSA), a histone deacetylase inhibitor, activated heparanase expression in promoter unmethylated LN229 and T98G cells but not in promoter methylated U251n cells. To identify the mechanisms of heparanase induction by 5-Aza-dC, heparanase expression-related transcription 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-methylation of histone H3 lysine K4 (H3K4me2) in LN229 and T98G cells. The increased histone acetylation and H3K4me2 were also observed in heparanaseexpressing tumor tissues by immunohistochemistry staining. Additionally, we found that nuclear factor κB (NFκB) p65 but not NFκB p50 was correlated with heparanase expression, which could be expressed both by neoplastic cells and angiogenesis-related neovessel cells. However, we did not observe any regulatory mechanism between heparanase and NFκB p65 via transient transfection of their cDNA in T98G and U251n cells. We concluded that heparanase expression is associated with histone modifications and promoter DNA methylation plays a role in the control of gene silencing. Overexpression of both heparanase and NFκB p65 may be the result of excessive histone modifications.

Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival

“…Hpse-KO cells originally appear capable of immediate early viral gene production, but late gene products are effectively absent ( Figure 1A ). These findings align with previous work from our group and others showing that active HPSE translocates to the nucleus and influences gene expression through an unknown mechanism ( 5 , 6 , 12 – 14 ). We therefore adopted an unbiased approach to generate a clearer understanding of how HPSE, or a lack thereof, potently influences gene expression and cell signaling to restrict viral production.…”

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

“…A corresponding decrease in nuclear heparan sulfate further confirms this observation (Figure 4C). Bearing in mind previous suggestions of the ability of HPSE to localize to the nucleus (Schubert et al, 2004; Nobuhisa et al, 2007), bind to DNA (Yang et al, 2015), and regulate chromatin modifications (He et al, 2012; Hong et al, 2012), we hypothesized that HPSE influences cytokine signaling by interaction with transcription factors. Indeed, western blot analysis of nuclear and cytoplasmic extracts from HCE cells (Figure 4D,E) and HeLa cells (Figure S3D) overexpressing GS3-HPSE showed significantly enhanced translocation of nuclear factor (NF)-κB to the nucleus upon infection.…”

DNA Methylation of Heparanase Promoter Influences Its Expression and Associated with the Progression of Human Breast Cancer

“…Thirdly, the regulation of heparanase is involved many factors in addition to cytosine methylation, including transcriptional and post-transcriptional regulation or other epigenetic mechanisms (e.g. histone modification, small non-coding RNA, environmental exposure induced methylation et al ) [45]–[47].…”