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Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts. Clin Cancer Res 2012 Aug 01;18(15):4070-9 PMID: 22675172 PMCID: PMC3716364

Pubmed ID

22675172

DOI

10.1158/1078-0432.CCR-12-0560

Abstract

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.

Author List

Kitange GJ, Mladek AC, Carlson BL, Schroeder MA, Pokorny JL, Cen L, Decker PA, Wu W, Lomberk GA, Gupta SK, Urrutia RA, Sarkaria JN

Authors

Gwen Lomberk PhD Associate Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-84864495476   66 Citations

MESH terms used to index this publication - Major topics in bold

Acetylation
Animals
Antineoplastic Agents, Alkylating
Blotting, Western
DNA Methylation
DNA Modification Methylases
DNA Repair Enzymes
Dacarbazine
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Glioblastoma
Histone Deacetylase Inhibitors
Histones
Humans
Hydroxamic Acids
Kaplan-Meier Estimate
Methylation
Mice
Promoter Regions, Genetic
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Proteins
Up-Regulation
Xenograft Model Antitumor Assays
jenkins-FCD Prod-321 98992d628744e349846c2f62ac68f241d7e1ea70