Clinical cancer research : an official journal of the American Association for Cancer ResearchJun 8, 2012

Blocking histone deacetylation may increase the development of drug resistance linked to MGMT in glioblastoma models

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 3, 2026

Abstract

Upregulation of O6-methylguanine-DNA methyltransferase (MGMT) expression was observed in 3 of the 5 resistant glioblastoma multiforme xenografts.

Temozolomide resistance in glioblastoma multiforme may be linked to increased MGMT expression.
No significant changes in MGMT promoter methylation were found between parental and resistant tumor samples.
An association was detected between MGMT upregulation and higher levels of acetylation of a specific histone mark (H3K9-ac) along with lower levels of another mark (H3K9-me2) in certain resistant tumors.
In one resistant line, increased MGMT expression correlated with greater recruitment of specific transcription factors to the MGMT promoter.
Combined treatment with temozolomide and an HDAC inhibitor may enhance MGMT overexpression, contributing to the development of resistance.

Simplified

PURPOSE: The therapeutic benefit of temozolomide in glioblastoma multiforme (GBM) is limited by resistance. The goal of this study was to elucidate mechanisms of temozolomide resistance in GBM.

EXPERIMENTAL DESIGN: We developed an in vivo GBM model of temozolomide resistance and used paired parental and temozolomide-resistant tumors to define the mechanisms underlying the development of resistance and the influence of histone deacetylation (HDAC) inhibition.

RESULTS: Analysis of paired parental and resistant lines showed upregulation of O6-methylguanine-DNA methyltransferase (MGMT) expression in 3 of the 5 resistant xenografts. While no significant change was detected in MGMT promoter methylation between parental and derivative-resistant samples, chromatin immunoprecipitation showed an association between MGMT upregulation and elevated acetylation of lysine 9 of histone H3 (H3K9-ac) and decreased dimethylation (H3K9-me2) in GBM12 and GBM14. In contrast, temozolomide resistance development in GBM22 was not linked to MGMT expression, and both parental and resistant lines had low H3K9-ac and high H3K9-me2 within the MGMT promoter. In the GBM12TMZ-resistant line, MGMT reexpression was accompanied by increased recruitment of SP1, C-JUN, NF-κB, and p300 within the MGMT promoter. Interestingly, combined treatment of GBM12 flank xenografts with temozolomide and the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) favored the evolution of temozolomide resistance by MGMT overexpression as compared with treatment with temozolomide alone.

CONCLUSION: This study shows, for the first time, a unique mechanism of temozolomide resistance development driven by chromatin-mediated MGMT upregulation and highlights the potential for epigenetically directed therapies to influence the mechanisms of resistance development in GBM.

Full Text

Full text is available at the source.

View Full Text ↗

Blocking histone deacetylation may increase the development of drug resistance linked to MGMT in glioblastoma models

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief