Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme

Abstract

BackgroundResistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient’s prognosis. Beside promoter methylation of the O 6 -methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM.MethodsTherefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples.ResultsDespite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM.ConclusionsIn summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients’ survival.

Effect of TET1 regulating MGMT on chemotherapy resistance of oral squamous cell carcinoma stem cells

“…Oct‐4, one of the POU‐domain transcription factors is expressed in pluripotent embryonic stem and germ cells . MGMT and ABCG2 were highlighted as fundamental factors contributing to drug resistance . We demonstrated in our study that low‐expression of TET1 in OSCC stem cells can stimulate MGMT promoter methylation.…”

“…29 MGMT and ABCG2 were highlighted as fundamental factors contributing to drug resistance. 30 We demonstrated in our study that low-expression of TET1 in OSCC stem cells can stimulate MGMT promoter methylation. Thus, based on various experimental data as well as scientific literature retrieved, we conclude that there are possible correlations between TET1 and ABCG2.…”

Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients

“…The eight CpGs in the ABCG2 promoter are overlapping with the CpGs targeted by To et al . [41] or in close distance to the regions investigated in previous studies [29, 31, 42]. The sequence to analyze has been predicted to contain a binding site for c-jun, a well-known proto-oncogene [48].…”

Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives

“…ABCB1 promoter methylation was reported to suppress ABCB1 mRNA and protein expression in tumor cells [64,65,66]. Hypomethylation of ABCB1 promoter was associated with poor response to clopidogrel in Chinese ischemic stroke patients with CYP2C19*1/*1 genotype [67].…”