scholarly journals Methylation-related chromatin structure is associated with exclusion of transcription factors from and suppressed expression of the O-6-methylguanine DNA methyltransferase gene in human glioma cell lines.

1994 ◽  
Vol 14 (10) ◽  
pp. 6515-6521 ◽  
Author(s):  
J F Costello ◽  
B W Futscher ◽  
R A Kroes ◽  
R O Pieper
Keyword(s):  
Transcription Factors ◽  
Cell Lines ◽  
Chromatin Structure ◽  
Glioma Cell ◽  
Dna Methyltransferase ◽  
Restriction Enzymes ◽  
Mgmt Expression ◽  
Mgmt Gene ◽  
Glioma Cell Lines

There is considerable interest in identifying factors responsible for expression of the O-6-methylguanine DNA methyltransferase (MGMT) gene, as MGMT is a major determinant in the response of glioma cells to the chemotherapeutic agent 1,3 bis(2-chloroethyl)-1-nitrosourea. Recently we have shown that MGMT expression is correlated in a direct, graded fashion with methylation in the body of the MGMT gene and in an inverse, graded fashion with promoter methylation in human glioma cell lines. To determine if promoter methylation is an important component of MGMT expression, this study addressed the complex interactions between methylation, chromatin structure, and in vivo transcription factor occupancy in the MGMT promoter of glioma cell lines with different levels of MGMT expression. Our results show that the basal promoter in MGMT-expressing glioma cell lines, which is 100% unmethylated, was very accessible to restriction enzymes at all sites tested, suggesting that this region may be nucleosome free. The basal promoter in glioma cells with minimal MGMT expression, however, which is 75% unmethylated, was much less accessible, and the basal promoter in nonexpressing cells, which is 50% unmethylated, was entirely inaccessible to restriction enzymes. Despite the presence of the relevant transcription factors in all cell lines examined, in vivo footprinting showed DNA-protein interactions at six Sp1 binding sites and one novel binding site in MGMT-expressing cell lines but no such interactions in nonexpressors. We conclude that in contrast to findings of previous in vitro studies, Sp1 is an important component of MGMT transcription. These correlations also strongly suggest that methylation and chromatin structure, by determining whether Sp1 and other transcription factors can access the MGMT promoter, set the transcriptional state of the MGMT gene.

Methylation-related chromatin structure is associated with exclusion of transcription factors from and suppressed expression of the O-6-methylguanine DNA methyltransferase gene in human glioma cell lines

1994 ◽  
Vol 14 (10) ◽  
pp. 6515-6521
Author(s):  
J F Costello ◽  
B W Futscher ◽  
R A Kroes ◽  
R O Pieper
Keyword(s):  
Transcription Factors ◽  
Cell Lines ◽  
Chromatin Structure ◽  
Glioma Cell ◽  
Dna Methyltransferase ◽  
Restriction Enzymes ◽  
Mgmt Expression ◽  
Mgmt Gene ◽  
Glioma Cell Lines

There is considerable interest in identifying factors responsible for expression of the O-6-methylguanine DNA methyltransferase (MGMT) gene, as MGMT is a major determinant in the response of glioma cells to the chemotherapeutic agent 1,3 bis(2-chloroethyl)-1-nitrosourea. Recently we have shown that MGMT expression is correlated in a direct, graded fashion with methylation in the body of the MGMT gene and in an inverse, graded fashion with promoter methylation in human glioma cell lines. To determine if promoter methylation is an important component of MGMT expression, this study addressed the complex interactions between methylation, chromatin structure, and in vivo transcription factor occupancy in the MGMT promoter of glioma cell lines with different levels of MGMT expression. Our results show that the basal promoter in MGMT-expressing glioma cell lines, which is 100% unmethylated, was very accessible to restriction enzymes at all sites tested, suggesting that this region may be nucleosome free. The basal promoter in glioma cells with minimal MGMT expression, however, which is 75% unmethylated, was much less accessible, and the basal promoter in nonexpressing cells, which is 50% unmethylated, was entirely inaccessible to restriction enzymes. Despite the presence of the relevant transcription factors in all cell lines examined, in vivo footprinting showed DNA-protein interactions at six Sp1 binding sites and one novel binding site in MGMT-expressing cell lines but no such interactions in nonexpressors. We conclude that in contrast to findings of previous in vitro studies, Sp1 is an important component of MGMT transcription. These correlations also strongly suggest that methylation and chromatin structure, by determining whether Sp1 and other transcription factors can access the MGMT promoter, set the transcriptional state of the MGMT gene.

scholarly journals Long Intergenic Noncoding RNA 00152 Promotes Glioma Cell Proliferation and Invasion by Interacting with MiR-16

2018 ◽  
Vol 46 (3) ◽  
pp. 1055-1064 ◽  
Author(s):  
Xin Chen ◽  
Deheng Li ◽  
Yang Gao ◽  
Wei Tang ◽  
Lao IW ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Glioma Cell ◽  
Migration And Invasion ◽  
Human Glioma ◽  
Human Glioma Cell ◽  
Glioma Cell Lines ◽  
Glioma Cell Proliferation ◽  
Proliferation And Invasion

Background/Aims: Long noncoding RNAs (lncRNAs) are a novel class of protein-noncoding transcripts that are aberrantly expressed in multiple diseases including cancers. LINC00152 has been identified as an oncogene involved in many kinds of cancer; however, its expression pattern and function in human glioma remain unclear. Methods: Quantitative real-time polymerase chain reaction was carried out to measure LINC00152 expression in human glioma cell lines and tissues. CCK-8 and EdU assays were performed to assess cell proliferation, and scratch assays and Transwell assays were used to assess cell migration and invasion, respectively. Luciferase reporter assays were carried out to determine the interaction between miR-16 and LINC00152. In vivo experiments were conducted to assess tumor formation. Results: LINC00152 was found to be significantly upregulated in human glioma cell lines and clinical samples. Knockdown of LINC00152 suppressed glioma cell proliferation, migration, and invasion in vitro. In vivo assays in nude mice confirmed that LINC00152 knockdown inhibits tumor growth. Furthermore, mechanistic investigation showed that LINC00152 binds to miR-16 in a sequence-specific manner and suppresses its expression. miR-16 inhibition strongly attenuated LINC00152 knockdown–mediated suppressive effects on proliferation, migration, and invasion. Moreover, LINC00152 induced BMI1 expression by sponging miR-16; this effect further promoted glioma cell proliferation and invasion. Conclusion: We regard LINC00152 as an oncogenic lncRNA promoting glioma cell proliferation and invasion and as a potential target for human glioma treatment.

scholarly journals Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma

2020 ◽  
pp. 1-10 ◽  
Author(s):  
Tetsuya Yamada ◽  
Shohei Tsuji ◽  
Shinsuke Nakamura ◽  
Yusuke Egashira ◽  
Masamitsu Shimazawa ◽  
...  
Keyword(s):  
Cell Lines ◽  
Dna Methyltransferase ◽  
Antitumor Effect ◽  
Metabotropic Glutamate Receptor ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase

OBJECTIVEGlutamatergic signaling significantly promotes proliferation, migration, and invasion in glioblastoma (GBM). Riluzole, a metabotropic glutamate receptor 1 inhibitor, reportedly suppresses GBM growth. However, the effects of combining riluzole with the primary GBM chemotherapeutic agent, temozolomide (TMZ), are unknown. This study aimed to investigate the efficacy of combinatorial therapy with TMZ/riluzole for GBM in vitro and in vivo.METHODSThree GBM cell lines, T98G (human; O6-methylguanine DNA methyltransferase [MGMT] positive), U87MG (human; MGMT negative), and GL261 (murine; MGMT positive), were treated with TMZ, riluzole, or a combination of both. The authors performed cell viability assays, followed by isobologram analysis, to evaluate the effects of combinatorial treatment for each GBM cell line. They tested the effect of riluzole on MGMT, a DNA repair enzyme causing chemoresistance to TMZ, through quantitative real-time reverse transcription polymerase chain reaction in T98G cells. Furthermore, they evaluated the efficacy of combinatorial TMZ/riluzole treatment in an orthotopic mouse allograft model of MGMT-positive GBM using C57BL/6 J mice and GL261 cells.RESULTSRiluzole displayed significant time- and dose-dependent growth-inhibitory effects on all GBM cell lines assessed independently. Riluzole enhanced the antitumor effect of TMZ synergistically in MGMT-positive but not in MGMT-negative GBM cell lines. Riluzole singularly suppressed MGMT expression, and it significantly suppressed TMZ-induced MGMT upregulation (p < 0.01). Furthermore, combinatorial TMZ/riluzole treatment significantly suppressed tumor growth in the intracranial MGMT-positive GBM model (p < 0.05).CONCLUSIONSRiluzole attenuates TMZ-induced MGMT upregulation and enhances the antitumor effect of TMZ in MGMT-positive GBMs. Therefore, combinatorial TMZ/riluzole treatment is a potentially promising novel therapeutic regimen for MGMT-positive GBMs.

scholarly journals CBMT-31. HDAC INHIBITION DIMINISHES THE GROWTH OF ENDOGENOUS IDH MUTANT GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi39-vi40
Author(s):  
Lubayna Elahi ◽  
Matthew Garrett ◽  
Lea Guo ◽  
Michael Condro ◽  
Riki Kawaguchi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Transcriptional Repression ◽  
Glioma Cell ◽  
Histone Deacetylase Inhibitors ◽  
Sequencing Analysis ◽  
Hdac Inhibition ◽  
In Vivo Experiments ◽  
Glioma Cell Lines

Abstract Histone deacetylase inhibitors (HDACi’s) have emerged as a promising class of drugs for treatment of malignancies such as glioblastoma (GBM). Several studies have demonstrated the anti-tumor property of HDACi’s against GBM in both in vitro and in vivo experiments. Nonetheless, in clinical trials, HDACi only marginally increased overall survival of patients with GBM. The mixed results of trials with HDACi’s in glioma have prompted us to hypothesize that improved selection of patients by tumor characteristics could enhance the efficacy of therapy. We specifically tested the effects of valproic acid (VPA), a HDACi and an antiepileptic drug against IDH mutant gliomas. We have previously demonstrated that our IDH mutant glioma cell lines have gene expression and methylation patterns highly similar to IDH mutant tumors in situ. Mutant IDH1 alters the epigenetic landscape of gliomas leading to the hypermethylation phenotype and transcriptional repression of genes. This repression of genes may contribute to tumorigenesis and progression of IDH mutant gliomas. We found that VPA inhibits the growth of patient-derived IDH1 mutant glioma lines. In addition, RNA sequencing analysis of vehicle and VPA-treated IDH1 mutant glioma cells showed de-repression of several genes previously shown to be downregulated in IDH1 mutant glioma cell lines. We also treated cells with another HDACi LBH589 and found that both VPA and LBH589 upregulates similar gene sets suggesting that HDAC inhibition promotes de-repression of previously repressed genes. Ongoing studies are aimed at determining the molecular mechanism by which VPA regulates the growth of IDH1 mutant tumors.

Chromatin structure in human glioma cell lines with different radiosensitivity

1997 ◽  
Vol 33 ◽  
pp. S25
Author(s):  
L. Schlenger ◽  
B. Flath ◽  
B. Sinn ◽  
V. Budach ◽  
A.E. Wurm
Keyword(s):  
Cell Lines ◽  
Chromatin Structure ◽  
Glioma Cell ◽  
Human Glioma ◽  
Human Glioma Cell ◽  
Glioma Cell Lines

Blocking of glioma proliferation in vitro and in vivo and potentiating the effects of BCNU and cisplatin: UCN-01, a selective protein kinase C inhibitor

1996 ◽  
Vol 84 (6) ◽  
pp. 1024-1032 ◽  
Author(s):  
Ian F. Pollack ◽  
Stephanie Kawecki ◽  
John S. Lazo
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Lines ◽  
Glioma Cell ◽  
Significant Activity ◽  
Inhibition Of Proliferation ◽  
Kinase C ◽  
Glioma Cell Lines

✓ Seven-hydroxystaurosporine (UCN-01) is a derivative of the nonselective protein kinase inhibitor staurosporine that exhibits significant selectivity for protein kinase C (PKC) in comparison to a variety of other intracellular kinases and appears to be well tolerated in vivo at concentrations sufficient to achieve effective inhibition of PKC. Because recent studies have indicated that the proliferation of malignant gliomas may result from activation of PKC-mediated pathways and, conversely, may be inhibited by blocking PKC, the authors examined the efficacy of this agent as an inhibitor of proliferation in three established and three low-passage malignant glioma cell lines in vitro. A striking inhibition of proliferation was produced by UCN-01 in each of the cell lines, with a median effective concentration of 20 to 100 nM, which correlated with the median in vitro PKC inhibitory concentration of 20 to 60 nM for this agent in the U-87 and SG-388 glioma cell lines. Inhibition-recovery studies of clonogenic activity indicated that UCN-01 had both cytostatic and cytotoxic effects on the treated cells. Proliferation resumed after short-term (6- and 24-hour) exposures to this agent; in contrast, with longer exposures, recovery of proliferative activity was severely compromised. In addition, UCN-01 enhanced the inhibition of glioma cell proliferation achieved with conventional chemotherapeutic agents, exhibiting synergistic effects with cisplatin and additive effects with 1,3-bis(2-chloroethyl)-1-nitrosourea. In vivo studies in which UCN-01 was administered by continuous intraperitoneal infusion in subcutaneous and intracranial intraparenchymal nude rat models demonstrated significant activity against U-87 glioma xenografts at dose levels that were well tolerated. It is concluded that UCN-01 is an effective agent for the inhibition of glioma proliferation in vitro and in vivo and has potential for clinical applicability in the treatment of human gliomas.

Abstract 4145: Brain-derived endothelial cells stimulate migration of different human, mouse, and rat glioma cell lines in vivo and in vitro

2015 ◽  
Author(s):  
Viveka N. Yadav ◽  
Gregory J. Baker ◽  
Samanthi Narayanan ◽  
Maria G. Castro ◽  
Pedro R. Lowenstein
Keyword(s):  
Endothelial Cells ◽  
Cell Lines ◽  
Glioma Cell ◽  
Rat Glioma ◽  
Glioma Cell Lines

Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression

2005 ◽  
Vol 73 (3) ◽  
pp. 189-198 ◽  
Author(s):  
Eva Bandres ◽  
Esther Andion ◽  
Alvaro Escalada ◽  
Beatriz Honorato ◽  
Victoria Catalan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Cell Lines ◽  
Expression Profile ◽  
Glioma Cell ◽  
Human Glioma ◽  
Mgmt Expression ◽  
Human Glioma Cell ◽  
Glioma Cell Lines
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