The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide

Erika L. Moen, Amy L. Stark, Wei Zhang, M. Eileen Dolan, Lucy A. Godley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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 inMGMTexpression 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 pretreated 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 pretreating patients whose tumors have an unmethylated MGMT promoter with decitabine before temozolomide treatment may increase their response to therapy.

Original languageEnglish (US)
Pages (from-to)1334-1344
Number of pages11
JournalMolecular cancer therapeutics
Volume13
Issue number5
DOIs
StatePublished - May 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide'. Together they form a unique fingerprint.

Cite this