MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression

Xu, Meixiang; Cross, Courtney E.; Speidel, Jordan T.; Abdel‐Rahman, Sherif Z.

doi:10.1007/s13402-016-0286-4

Cited by 7 publications

(7 citation statements)

References 48 publications

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“…A case in point is the G-1157aA, which when found in haplotype 30, it produced a significant decrease in promoter activity, however, when G-1157aA is found alone (haplotype M4), the activity was significantly increased, indicating that single SNPs are not always the phenotype drivers. This corroborates our earlier observations involving the O-6-methylguanine DNA methyltransferase (MGMT) gene [20,21]. In these studies, we found the MGMT promoter SNP C575A (rs113813075) may have no effect in one haplotype but can have dramatic effects on MGMT expression when found in another haplotype.…”

Section: Discussionsupporting

confidence: 92%

“…Alternatively, the G-240A variant could generate a higher affinity binding site for a transcription activator or alter the secondary structure of the DNA. Additional support to this hypothesis is provided by our previous work with MGMT [20,21]. In these studies, we observed haplotype-dependent TF binding profiles that significantly correlated with MGMT promoter activity [21].…”

Section: Discussionsupporting

confidence: 75%

“…Thus, several SNPs, creating specific haplotypes, act in concert to provide the observed variability in response to an exposure. Recently, we reported the phenotypic effect of a SNP is not always consistent and varies depending on its presence within a specific haplotype [20,21]. Therefore, genotyping of a single or a few individual SNPs may fail to capture true functionality of genetic variants.…”

Section: Introductionmentioning

confidence: 99%

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Differential effect of ABCB1 haplotypes on promoter activity

Speidel

Abdel‐Rahman

2018

Pharmacogenetics and Genomics

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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Differential effect of ABCB1 haplotypes on promoter activity

Speidel

Abdel‐Rahman

2018

Pharmacogenetics and Genomics

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“…We can take advantage here from our work, which could be a potential target that can help overcome the unmethylated patients’ resistance to TMZ. Interestingly, Xu et al [ 23 ] recently found that haplotype has an impact on transcription factor binding in the MGMT promoter/enhancer region consequently regulating MGMT expression. This finding may help our work on Gli1 to fit better on evaluating MGMT activity.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog/Gli1 signaling pathway regulates MGMT expression and chemoresistance to temozolomide in human glioblastoma

et al. 2017

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BackgroundChemoresistance of glioblastoma (GBM) is a feature of this devastating disease. This study is to determine the relationship between Hedgehog (HH)/Gli1 signaling pathway and chemoresistance to temozolomide (TMZ) in human GBM.MethodsWe analyzed Gli1 nuclear staining and O6-methylguanine DNA methyltransferase (MGMT) expression in 48 cases of primary GBM tissues by immunohistochemistry. Quantitative PCR, western blot, methylation-specific PCR, cell proliferation and apoptosis assay were used to investigate changes of MGMT expression and chemosensitivity to TMZ after manipulating HH/Gli1 signaling activity in A172 and U251 GBM cell lines. Chromatin immunoprecipitation assay was utilized to identify potential Gli1 potential binding sites in MGMT gene promoter region. We established GBM xenografts using U251 cells to assess whether inhibiting HH/Gli1 signaling activity restored chemosensitivity to TMZ.ResultsO6-Methylguanine DNA methyltransferase-positive GBM tissues had a significantly higher rate of Gli1 nuclear staining than MGMT-negative ones (67.7% vs. 32.3%, p = 0.0159). Activation of HH/Gli1 signaling by pcDNA3.1-Gli1 cell transfection in A172 cells led to increased MGMT expression and enhanced resistance to TMZ treatment. Inhibition of the HH/Gli1 signaling by cyclopamine in U251 cells resulted in decreased MGMT expression and increased sensitivity to TMZ treatment. Both ways altered MGMT levels without changing the MGMT promoter methylation. The potential binding site of Gli1 in the MGMT gene promoter region was located at – 411 to − 403 bp upstream the transcriptional start site. The in vivo study revealed a synergistic effect on tumor growth inhibition with the combined administration of cyclopamine and TMZ.ConclusionsThis study shows that HH/Gli1 signaling pathway regulates MGMT expression and chemoresistance to TMZ in human GBM independent from MGMT promoter methylation status, which offers a potential target to restore chemosensitivity to TMZ in a fraction of GBM with high MGMT expression.

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“…RLU, relative light units; siRNA, small interfering RNA. Color images available online at www.liebertpub.com/dna with recent data from our laboratory that indicated that different haplotypes alter the binding of TFs to the MGMT promoter and, subsequently, affect its promoter activity and expression level (Xu et al, 2016). The siRNA studies with haplotype 30, which has very low basal promoter activity, revealed that none of the tested siRNAs had any effect on its activity (Fig.…”

Section: Figmentioning

confidence: 62%

Promoter Haplotypes of theABCB1Gene Encoding the P-Glycoprotein Differentially Affect Its Promoter Activity by Altering Transcription Factor Binding

Speidel

Abdel‐Rahman

2018

DNA and Cell Biology

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Promoter single nucleotide polymorphisms (SNPs) of the ABCB1 gene, encoding the placental efflux transporter P-glycoprotein, can alter its expression and affect fetal exposure to therapeutics and environmental xenobiotics. SNPs are not arrayed as independent variants but as combinations forming defined haplotypes. Recently, we defined the haplotypes encompassing ABCB1 promoter SNPs and found that ABCB1 haplotypes differentially affect its promoter activity. The mechanism(s) by which ABCB1 haplotypes alter its promoter activity are not known. We hypothesize that the haplotype-dependent differences in ABCB1 promoter activity are due to haplotype-specific alterations in transcription factor (TF) binding. To test our hypothesis, we used a TF binding profile array and determined whether differences in TF binding exist across different ABCB1 haplotypes. TFs showing significant haplotype binding differences were mechanistically evaluated using small interfering RNA (siRNA) in cultured human placental cells. Our data indicate significant haplotype-dependent differences in TF binding. Our siRNA studies showed that the regulatory effects of TFs on promoter activity are also haplotype dependent. Our data provide a mechanistic explanation for the differential effects of ABCB1 haplotypes on its promoter activity and underscore the importance of evaluating genetic variants in the context of haplotypes rather than individual SNPs when investigating their effects on gene/protein expression and disease risk.

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MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression

Abstract: The data generated support our hypothesis that promoter haplotypes alter the binding of TFs to the MGMT P/E and, subsequently, affect their regulatory function on MGMT promoter activity and expression level.

Cited by 7 publications

References 48 publications

Differential effect of ABCB1 haplotypes on promoter activity

Differential effect of ABCB1 haplotypes on promoter activity

Hedgehog/Gli1 signaling pathway regulates MGMT expression and chemoresistance to temozolomide in human glioblastoma

Promoter Haplotypes of theABCB1Gene Encoding the P-Glycoprotein Differentially Affect Its Promoter Activity by Altering Transcription Factor Binding

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