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Inhibition of Histone Deacetylation Potentiates the Evolution of Acquired Temozolomide Resistance Linked to MGMT Upregulation in Glioblastoma Xenografts
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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. Clin Cancer Res; 18(15); 4070–9. ©2012 AACR.
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“HDAC inhibitor SAHA shows strong effects in destabilizing mut-p53 by dissociating HDAC6 from functional interaction with Hsp90 and thereby inhibits GBM growth and resistance to chemotherapy [142,143,144,145,146].”
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Metadata
- Authors
- Kitange, G. J., Mladek, A. C., Carlson, B. L., Schroeder, M. A., Pokorny, J. L., Cen, L., Decker, P. A., Wu, W., Lomberk, G. A., Gupta, S. K., Urrutia, R. A., & Sarkaria, J. N.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Kitange, Gaspar J.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2012-07-30
- Volume
- 18
- Issue
- 15
- Pages
- 4070-4079
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3716364
- OpenAlex
- W2135891497
- Cited by
- 151
- References
- 33
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 14 · 2023: 14 · 2022: 9 · 2021: 14 · 2020: 9 · 2019: 13 · 2018: 14 · 2017: 8 · 2016: 10 · 2015: 14 · 2014: 12 · 2013: 7 · 2012: 2
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Mayo Clinic
- National Cancer Institute (R01CA127716, R01CA141121, P50CA108961)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK052913)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- temozolomide resistance, glioblastoma, histone deacetylase inhibition, O6-methylguanine-DNA methyltransferase, histone H3 lysine 9 acetylation, H3K9me2, MGMT promoter, chromatin remodeling, Sp1, NF-κB, P300, vorinostat, epigenetic therapy, xenograft models
- MeSH terms
- Temozolomide, Vorinostat, Acetylation, Animals, Dacarbazine, Glioblastoma, Histones, Humans, Hydroxamic Acids, Methylation, Promoter Regions, Genetic, Blotting, Western, DNA Modification Methylases, Up-Regulation, Gene Expression Regulation, Neoplastic, Antineoplastic Agents, Alkylating, Drug Resistance, Neoplasm, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays, Tumor Suppressor Proteins, DNA Repair Enzymes, Mice, Kaplan-Meier Estimate, Histone Deacetylase Inhibitors
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