Global and Regional DNA methylation silencing of PPARγ Associated with Glioblastoma Multiforme Pathogenesis

Background The relationship between peroxisome proliferator-activated receptor gamma (PPAR gamma) expression level and epigenetic modifications occurring in glioblastoma multiforme (GBM) pathogenesis is largely unknown. Herein, we examine the association of PPAR gamma expression with its promoter and genomic global DNA methylation status, as well as DNA methyltransferases (DNMTs) gene expression in GBM patients. Methods We examined the patterns of promoter methylation and PPAR gamma expression in 26 GBM tissues and 13 adjacent non-tumor tissues by methylation-specific PCR (MSP), real-time PCR, and ELISA, respectively. Also, we examined the genomic global 5-methyl cytosine levels and DNMTs gene expression using ELISA and real-time PCR methods, respectively. Results We found that hypermethylation on a specific region of the PPAR gamma promoter is significantly associated with the downregulation of the PPAR gamma gene and protein level in GBM patients. Interestingly, the amount of 5-methyl cytosine level was significantly reduced in GBM patients and positively correlated with PPAR gamma protein expression. Furthermore, the expression level of DNMT1, DNMT3A, and 3B were upregulated in GBM patients and the average expression level of all three DNMTs was positively correlated with tumor area. Also, we found that tumors from cortical regions exhibited a higher global DNA hypomethylation and PPAR gamma hypermethylation was related to the increase in GBM risk. Conclusion Our study demonstrated that global DNA methylation and PPAR gamma epigenetic silencing is associated with the GBM risk. Our data provide a novel molecular mechanistic insight into epigenetic silencing of PPAR gamma in GBM patients that may be relevant as a key tumor marker for GBM pathogenesis.

Automated summary

In this study, the relationship between peroxisome proliferator-activated receptor gamma (PPAR gamma) expression level and epigenetic modifications occurring in glioblastoma multiforme (GBM) pathogenesis was investigated. The results showed that hypermethylation of a specific region of the PPAR gamma promoter is associated with the downregulation of the PPAR gamma gene and protein level in GBM patients. Additionally, global DNA methylation was found to be reduced in GBM patients and positively correlated with PPAR gamma protein expression. Furthermore, the expression levels of DNMT1, DNMT3A, and DNMT3B were upregulated in GBM patients and positively correlated with tumor area. The study also revealed that cortical tumors exhibited higher global DNA hypomethylation and PPAR gamma hypermethylation was associated with an increased GBM risk.