The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide
Menée sur 91 échantillons tumoraux prélevés sur des patients atteints d'un glioblastome, puis sur des lignées cellulaires, cette étude suggère l'intérêt de la décitabine, chez les patients dont les tumeurs présentent un promoteur non méthylé du gène MGMT, pour augmenter l'efficacité d'un traitement à l'aide de témozolomide
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is known to play a role in sensitivity to temozolomide. Promoter hypermethylation of MGMT is commonly used to predict low expression levels of MGMT in gliomas, despite observed discordance between promoter methylation and protein levels. Here, we investigated the functional role of gene body cytosine modification in regulating levels of MGMT gene expression and sensitivity to temozolomide. In 91 human glioblastoma samples, we observed significant variation in MGMT expression levels in patients with an unmethylated promoter, with higher levels of gene body cytosine modification correlating with higher gene expression levels. Furthermore, inducing hypomethylation across the MGMT gene body with decitabine corresponded with decreased levels of MGMT gene expression in lymphoblastoid and glioblastoma cell lines, indicating an important functional role for gene body cytosine modifications in maintaining gene expression. We reasoned that the decrease in MGMT expression induced by decitabine may render resistant glioblastoma cell lines more sensitive to temozolomide. Consistent with this reasoning, we found that the MGMT-expressing glioblastoma cell lines exhibiting an unmethylated MGMT promoter that were pre-treated with decitabine became significantly more sensitive to temozolomide. Overall, our results suggest a functional role for gene body cytosine modification in regulating gene expression of MGMT and indicate that pre-treating patients whose tumors have an unmethylated MGMT promoter with decitabine prior to temozolomide treatment may increase their response to therapy.
http://mct.aacrjournals.org/content/early/2014/02/25/1535-7163.MCT-13-0924.abstract