title: Heparanase expression is associated with histone modifications in glioblastoma.
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 heparanase-expressing 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.
authors: Department of Neurosurgery, Henry Ford Health System, 2799 W                     Grand Blvd, Detroit, MI 48202, USA.
authors: Xin
authors: X
authors: Hong
authors: Kevin
authors: K
authors: Nelson
authors: Nancy
authors: N
authors: Lemke
authors: Steven N
authors: SN
authors: Kalkanis
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D018899:CpG Islands; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D044127:Epigenesis, Genetic; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008969:Molecular Sequence Data; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D051996:Transcription Factor RelA / Q000378:metabolism; D000099175:Heparanase
chemical_list: D001374:Azacitidine; D015254:DNA Modification Methylases; D000077209:Decitabine; D005966:Glucuronidase; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D000099175:Heparanase; C498143:RELA protein, human; C012589:trichostatin A