We are analyzing https://link.springer.com/article/10.1007/s00401-013-1081-1.

Title:
In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing | Acta Neuropathologica
Description:
Favorable outcome after chemotherapy of glioblastomas cannot unequivocally be linked to promoter hypermethylation of the O 6-methylguanine-DNA methyltransferase (MGMT) gene encoding a DNA repair enzyme associated with resistance to alkylating agents. This indicates that molecular mechanisms determining MGMT expression have not yet been fully elucidated. We here show that glioblastomas are capable to downregulate MGMT expression independently of promoter methylation by elongation of the 3′-UTR of the mRNA, rendering the alternatively polyadenylated transcript susceptible to miRNA-mediated suppression. While the elongated transcript is poorly expressed in normal brain, its abundance in human glioblastoma specimens is inversely correlated with MGMT mRNA expression. Using a bioinformatically guided experimental approach, we identified miR-181d, miR-767-3p, and miR-648 as significant post-transcriptional regulators of MGMT in glioblastomas; the first two miRNAs induce MGMT mRNA degradation, the latter affects MGMT protein translation. A regression model including the two miRNAs influencing MGMT mRNA expression and the MGMT methylation status reliably predicts The Cancer Genome Atlas MGMT expression data. Responsivity of MGMT expressing T98G glioma cells to temozolomide was significantly enhanced after transfection of miR-181d, miR-767-3p, and miR-648. Taken together, our results uncovered alternative polyadenylation of the MGMT 3′-UTR and miRNA targeting as new mechanisms of MGMT silencing.
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Keywords {🔍}

mgmt, article, google, scholar, pubmed, cas, expression, kreth, glioblastoma, human, polyadenylation, gene, methylation, alternative, mrna, cancer, temozolomide, glioblastomas, cells, cell, silencing, promoter, glioma, access, regions, microrna, munich, privacy, cookies, content, research, acta, mirna, dna, oncol, data, information, publish, search, transcript, targeting, january, limbeck, ludwig, hinske, thon, egensperger, methyltransferase, weller, nature,

Topics {✒️}

month download article/chapter dna-repair gene mgmt o6-methylguanine dna methyltransferase o-methylguanine-dna methyltransferase methylguanine-dna methyltransferase mgmt significant post-transcriptional regulators determining gene expression mgmt mrna expression full article pdf mgmt promoter methylation downregulates mgmt expression distinct cpg regions privacy choices/manage cookies mgmt gene silencing human mrna polyadenylation 6-methylguanine-dna methyltransferase methylguanine-dna-methyltransferase dna repair enzyme poor dna methylation promoter cpg island mirna-mediated suppression mgmt methylation analysis histone deacetylation potentiates malignant glioma independent human microrna targets human glioblastoma specimens microrna binding sites article kreth gene expression nonconserved microrna targets predictive glioblastoma biomarker polyadenylation activates oncogenes european economic area regression model including mouse embryonic fibroblasts drosophila s2-cells mouse embryonic development pluripotent stem cells pattern-based method eortc-ncic trial liver-type glutaminase expert technical assistance conditions privacy policy identified mir-181d mgmt expression el naqa im check access instant access post-transcriptional regulation article log

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         headline:In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing
         description:Favorable outcome after chemotherapy of glioblastomas cannot unequivocally be linked to promoter hypermethylation of the O 6-methylguanine-DNA methyltransferase (MGMT) gene encoding a DNA repair enzyme associated with resistance to alkylating agents. This indicates that molecular mechanisms determining MGMT expression have not yet been fully elucidated. We here show that glioblastomas are capable to downregulate MGMT expression independently of promoter methylation by elongation of the 3′-UTR of the mRNA, rendering the alternatively polyadenylated transcript susceptible to miRNA-mediated suppression. While the elongated transcript is poorly expressed in normal brain, its abundance in human glioblastoma specimens is inversely correlated with MGMT mRNA expression. Using a bioinformatically guided experimental approach, we identified miR-181d, miR-767-3p, and miR-648 as significant post-transcriptional regulators of MGMT in glioblastomas; the first two miRNAs induce MGMT mRNA degradation, the latter affects MGMT protein translation. A regression model including the two miRNAs influencing MGMT mRNA expression and the MGMT methylation status reliably predicts The Cancer Genome Atlas MGMT expression data. Responsivity of MGMT expressing T98G glioma cells to temozolomide was significantly enhanced after transfection of miR-181d, miR-767-3p, and miR-648. Taken together, our results uncovered alternative polyadenylation of the MGMT 3′-UTR and miRNA targeting as new mechanisms of MGMT silencing.
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            Alternative polyadenylation
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      headline:In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing
      description:Favorable outcome after chemotherapy of glioblastomas cannot unequivocally be linked to promoter hypermethylation of the O 6-methylguanine-DNA methyltransferase (MGMT) gene encoding a DNA repair enzyme associated with resistance to alkylating agents. This indicates that molecular mechanisms determining MGMT expression have not yet been fully elucidated. We here show that glioblastomas are capable to downregulate MGMT expression independently of promoter methylation by elongation of the 3′-UTR of the mRNA, rendering the alternatively polyadenylated transcript susceptible to miRNA-mediated suppression. While the elongated transcript is poorly expressed in normal brain, its abundance in human glioblastoma specimens is inversely correlated with MGMT mRNA expression. Using a bioinformatically guided experimental approach, we identified miR-181d, miR-767-3p, and miR-648 as significant post-transcriptional regulators of MGMT in glioblastomas; the first two miRNAs induce MGMT mRNA degradation, the latter affects MGMT protein translation. A regression model including the two miRNAs influencing MGMT mRNA expression and the MGMT methylation status reliably predicts The Cancer Genome Atlas MGMT expression data. Responsivity of MGMT expressing T98G glioma cells to temozolomide was significantly enhanced after transfection of miR-181d, miR-767-3p, and miR-648. Taken together, our results uncovered alternative polyadenylation of the MGMT 3′-UTR and miRNA targeting as new mechanisms of MGMT silencing.
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         MGMT
         Alternative polyadenylation
         miRNA
         Pathology
         Neurosciences
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