Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts.
Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts.
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DOI：
10.1158/1078-0432.ccr-12-0560
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发表时间：
2012-08-01
期刊：
影响因子：
--
通讯作者：
Sarkaria JN
中科院分区：
文献类型：
--
作者：
Kitange GJ;Mladek AC;Carlson BL;Schroeder MA;Pokorny JL;Cen L;Decker PA;Wu W;Lomberk GA;Gupta SK;Urrutia RA;Sarkaria JN
The therapeutic benefit of temozolomide (TMZ) in glioblastoma (GBM) is limited by resistance. The goal of this study was to elucidate mechanisms of TMZ resistance in GBM. We developed an in vivo GBM model of TMZ resistance and used paired parental and TMZ resistant tumors to define the mechanisms underlying the development of resistance and the influence of histone deacetylation (HDAC) inhibition. Analysis of paired parental and resistant lines demonstrated upregulation of 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 demonstrated an association between MGMT upregulation and elevated acetylation of lysine 9 of histone H3 (H3K9-ac) and decreased di-methylation (H3K9-me2) in GBM12 and GBM14. In contrast, TMZ 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 GBM12 TMZ resistant line, MGMT re-expression was accompanied by increased recruitment of SP1, C-JUN, NF-kB and p300 within the MGMT promoter. Interestingly, combined treatment of GBM12 flank xenografts with TMZ and the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) favored the evolution of TMZ resistance by MGMT over-expression as compared to treatment with TMZ alone. This study demonstrates, for the first time, a unique mechanism of TMZ 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.
