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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].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [143]
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Cites
Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma
Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J. B., Belanger, K., Brandes, A. A., Marosi, C., Bogdahn, U., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043330 · Cited by 21,807
MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma
Hegi, M. E., Diserens, A.-C., Gorlia, T., Hamou, M.-F., de Tribolet, N., Weller, M., Kros, J. M., Hainfellner, J. A., Mason, W., Mariani, L., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043331 · Cited by 7,405
Pollard, S. M., Yoshikawa, K., Clarke, I. D., Danovi, D., Stricker, S., Russell, R., Bayani, J., Head, R., Lee, M., Bernstein, M., et al. (2009) · Cell Stem Cell · doi:10.1016/j.stem.2009.03.014 · Cited by 1,025
MGMT: its role in cancer aetiology and cancer therapeutics
Gerson, S. L. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1319 · Cited by 817
Hegi, M. E., Liu, L., Herman, J. G., Stupp, R., Wick, W., Weller, M., Mehta, M. P., & Gilbert, M. R. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.11.5964 · Cited by 811
MGMT promoter methylation in malignant gliomas: ready for personalized medicine?
Weller, M., Stupp, R., Reifenberger, G., Brandes, A. A., van den Bent, M. J., Wick, W., & Hegi, M. E. (2009) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.197 · Cited by 803
Hegi, M. E., Diserens, A., Godard, S., Dietrich, P.-Y., Regli, L., Ostermann, S., Otten, P., van Melle, G., de Tribolet, N., & Stupp, R. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0384 · Cited by 782
Clinical Relevance of MGMT in the Treatment of Cancer
Gerson, S. L. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.2002.06.110 · Cited by 429
Yip, S. S. F., Miao, J., Cahill, D. P., Iafrate, A. J., Aldape, K., Nutt, C. L., & Louis, D. N. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-3012 · Cited by 413
Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts
Kitange, G. J., Carlson, B. L., Schroeder, M. A., Grogan, P. T., Lamont, J. D., Decker, P. A., Wu, W., James, C. D., & Sarkaria, J. N. (2008) · Neuro-Oncology · doi:10.1215/15228517-2008-090 · Cited by 387
Self-citationMechanisms of Chemoresistance to Alkylating Agents in Malignant Glioma
Sarkaria, J. N., Kitange, G. J., James, C. D., Plummer, R., Calvert, H., Weller, M., & Wick, W. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1719 · Cited by 384
Self-citationGiannini, C., Sarkaria, J. N., Saito, A., Uhm, J. H., Galanis, E., Carlson, B. L., Schroeder, M. A., & James, C. D. (2005) · Neuro-Oncology · doi:10.1215/s1152851704000821 · Cited by 326
Self-citationHistone modification and the control of heterochromatic gene silencing in Drosophila
Ebert, A., Lein, S., Schotta, G., & Reuter, G. (2006) · Chromosome Research · doi:10.1007/s10577-006-1066-1 · Cited by 214
Chinot, O. L., Barrié, M., Fuentes, S., Eudes, N., Lancelot, S., Métellus, P., Muracciole, X., Braguer, D., Ouafik, L., Martin, P., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.07.4807 · Cited by 208
Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas
Everhard, S., Tost, J., abdalaoui, H. E., Crinière, E., Busato, F., Marie, Y., Gut, I. G., Sanson, M., Mokhtari, K., Laigle–Donadey, F., et al. (2009) · Neuro-Oncology · doi:10.1215/15228517-2009-001 · Cited by 177
Gaspar, N., Marshall, L. V., Perryman, L., Bax, D. A., Little, S. E., Viana‐Pereira, M., Sharp, S. Y., Vassal, G., Pearson, A. D. J., Reis, R. M., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1250 · Cited by 167
Raynal, N. J. ‐., Si, J., Taby, R. F., Gharibyan, V., Ahmed, S., Jelı́nek, J., Estecio, M. R., & Issa, J. J. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3248 · Cited by 135
Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule
Perry, J., Rizek, P., Cashman, R. L., Morrison, M., & Morrison, T. (2008) · Cancer · doi:10.1002/cncr.23813 · Cited by 122
van Nifterik, K. A., van den Berg, J., van der Meide, W. F., Ameziane, N., Wedekind, L. E., Steenbergen, R. D. M., Leenstra, S., Lafleur, M. V. M., Slotman, B. J., Stalpers, L. J. A., et al. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605712 · Cited by 116
Wiewrodt, D., Nagel, G., Dreimüller, N., Hundsberger, T., Perneczky, A., & Kaina, B. (2008) · International Journal of Cancer · doi:10.1002/ijc.23219 · Cited by 114
Zhang, J., Stevens, M. F. G., Laughton, C. A., Madhusudan, S., & Bradshaw, T. D. (2010) · Oncology · doi:10.1159/000306139 · Cited by 110
Naumann, S. C., Roos, W. P., Jöst, E., Belohlavek, C., Lennerz, V., Schmidt, C., Christmann, M., & Kaina, B. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6604856 · Cited by 101
Kitange, G. J., Carlson, B. L., Mladek, A. C., Decker, P. A., Schroeder, M. A., Wu, W., Grogan, P. T., Giannini, C., Ballman, K. V., Buckner, J. C., et al. (2008) · Journal of Neuro-Oncology · doi:10.1007/s11060-008-9737-8 · Cited by 97
Self-citationClarke, M. J., Mulligan, E. A., Grogan, P. T., Mladek, A. C., Carlson, B. L., Schroeder, M. A., Curtin, N. J., Lou, Z., Decker, P. A., Wu, W., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0854 · Cited by 96
Self-citationSpiegl‐Kreinecker, S., Pirker, C., Filipits, M., Lötsch, D., Buchroithner, J., Pichler, J., Silye, R., Weis, S., Micksche, M., Fischer, J., et al. (2009) · Neuro-Oncology · doi:10.1093/neuonc/nop003 · Cited by 88
Carlson, B. L., Grogan, P. T., Mladek, A. C., Schroeder, M. A., Kitange, G. J., Decker, P. A., Giannini, C., Wu, W., Ballman, K. V., James, C. D., et al. (2009) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2009.04.026 · Cited by 87
Self-citationKong, D., Lee, J.-I., Kim, W. K., Son, M. J., Lim, D. H., Kim, S. H., Park, K., Kim, J. W., Eoh, W., & Nam, D. (2006) · Oncology Reports · doi:10.3892/or.16.5.1117 · Cited by 70
Zhao, W. (2005) · The Journal of Biochemistry · doi:10.1093/jb/mvi048 · Cited by 61
Hirose, Y., Kreklau, E. L., Erickson, L. C., Berger, M. S., & Pieper, R. O. (2003) · Journal of neurosurgery · doi:10.3171/jns.2003.98.3.0591 · Cited by 39
Temozolomide and carmustine cause large-scale heterochromatin reorganization in glioma cells
Papait, R., Magrassi, L., Rigamonti, D., & Cattaneo, E. F. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.12.091 · Cited by 35
MSH6 inactivation and emergent temozolomide resistance in human glioblastomas.
Cahill, D. P., Codd, P. J., Batchelor, T. T., Curry, W. T., & Louis, D. N. (2008) · PubMed · Cited by 30
Ishii, D., Natsume, A., Wakabayashi, T., Hatano, H., Asano, Y., TAKEUCHI, H., Shimato, S., Ito, M., Fujii, M., & Yoshida, J. (2007) · Neurologia medico-chirurgica · doi:10.2176/nmc.47.341 · Cited by 28
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Alifieris, C. E., & Trafalis, D. T. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.05.005 · Cited by 859
MGMT testing—the challenges for biomarker-based glioma treatment
Wick, W., Weller, M., van den Bent, M. J., Sanson, M., Weiler, M., von Deimling, A., Plass, C., Hegi, M. E., Platten, M., & Reifenberger, G. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.100 · Cited by 599
The p53 Pathway in Glioblastoma
Zhang, Y., Dube, C., Gibert, M., Cruickshanks, N., Wang, B., Coughlan, M., Yang, Y., Setiady, I., Deveau, C., Saoud, K., et al. (2018) · Cancers · doi:10.3390/cancers10090297 · Cited by 440
Lu, C., Wei, Y., Wang, X., Zhang, Z., Yin, J., Li, W., Chen, L., Lyu, X., Shi, Z., Yan, W., et al. (2020) · Molecular Cancer · doi:10.1186/s12943-020-1137-5 · Cited by 303
Poised epigenetic states and acquired drug resistance in cancer
Brown, R., Curry, E., Magnani, L., Wilhelm-Benartzi, C. S., & Borley, J. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3819 · Cited by 301
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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