Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrant activation of wingless (Wnt) signaling is involved in the pathogenesis of various cancers. Recent studies suggested a role of Wnt signaling in gliomas, the most common primary brain tumors. We investigated 70 gliomas of different malignancy grades for promoter hypermethylation in 8 genes encoding members of the secreted frizzled-related protein (SFRP1, SFRP2, SFRP4, SFRP5), dickkopf (DKK1, DKK3) and naked (NKD1, NKD2) families of Wnt pathway inhibitors. All tumors were additionally analyzed for mutations in exon 3 of the beta-catenin gene (CTNNB1). While none of the tumors carried CTNNB1 mutations, we found frequent promoter hypermethylation of Wnt pathway inhibitor genes, with at least one of these genes being hypermethylated in 6 of 16 diffuse astrocytomas (38%), 4 of 14 anaplastic astrocytomas (29%), 7 of 10 secondary glioblastomas (70%) and 23 of 30 primary glioblastomas (77%). Glioblastomas often demonstrated hypermethylation of 2 or more analyzed genes. Hypermethylation of SFRP1, SFRP2 and NKD2 each occurred in more than 40% of the primary glioblastomas, while DKK1 hypermethylation was found in 50% of secondary glioblastomas. Treatment of SFRP1-, SFRP5-, DKK1-, DKK3-, NKD1- and NKD2-hypermethylated U87-MG glioblastoma cells with 5-aza-2'-deoxycytidine and trichostatin A resulted in increased expression of each gene. Furthermore, SFRP1-hypermethylated gliomas showed significantly lower expression of the respective transcripts when compared with unmethylated tumors. Taken together, our results suggest an important role of epigenetic silencing of Wnt pathway inhibitor genes in astrocytic gliomas, in particular, in glioblastomas, with distinct patterns of hypermethylated genes distinguishing primary from secondary glioblastomas.
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PMID:Frequent promoter hypermethylation of Wnt pathway inhibitor genes in malignant astrocytic gliomas. 1984 10

The still largely obscure molecular events in the glioblastoma oncogenesis, a primary brain tumor characterized by an inevitably dismal prognosis, impel for investigation. The importance of Long noncoding RNAs as regulators of gene expression has recently become evident. Among them, H19 has a recognized oncogenic role in several types of human tumors and was shown to correlate to some oncogenic aspects of glioblastoma cells. Here we, hypothesyze that in glioblastoma H19 exerts its function through the interaction with the catalytic subunit of the PRC2 complex, EZH2. By employing a factor analysis on a SAGE dataset of 12 glioblastoma samples, we show that H19 expression in glioblastoma tissues correlates with that of several genes involved in glioblastoma growth and progression. H19 knock-down reduces viability, migration and invasiveness of two distinct human glioblastoma cell lines. Most importantly, we provide a mechanistic perspective about the role of H19 in glioblastoma cells, by showing that its expression is inversely linked to that of NKD1, a negative regulator of Wnt pathway, suggesting that H19 might regulate NKD1 transcription via EZH2-induced H3K27 trimethylation of its promoter. Indeed, we showed that H19 binds EZH2 in glioblastoma cells, and that EZH2 binding to NKD1 and other promoters is impaired by H19 silencing. In this work we describe H19 as part of an epigenetic modulation program executed by EZH2, that results in the repression of Nkd1. We believe that our results can provide a new piece to the complex puzzle of H19 function in glioblastoma.
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PMID:The lncRNA H19 positively affects the tumorigenic properties of glioblastoma cells and contributes to NKD1 repression through the recruitment of EZH2 on its promoter. 2964 89