BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression
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PROVIDER: PRJNA899453 | ENA |
REPOSITORIES: ENA
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Project description:Two cell lines were used for methylation profiling to investigate how BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression
2022-12-21 | GSE217515 | GEO
Project description:Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs. Hence, epigenetic reprogramming strategies are desperately needed in order to enhance TMZ response in both MGMT-M and MGMT-UM GBMs. In this study, we present novel evidence that the epigenetic reactivation of Tumor Suppressor Candidate 3 (TUSC3) can reprogram sensitivity of GBM stem cells (GSCs) to TMZ irrespective of MGMT promoter methylation status. Interrogation of TCGA patient GBM datasets confirmed TUSC3 promoter regulation of TUSC3 expression and also revealed a strong positive correlation between TUSC3 expression and GBM patient survival. Using a combination of loss-of-function, gain-of-function and rescue studies, we demonstrate that TUSC3 reactivation is associated with enhanced TMZ response in both MGMT-M and MGMT-UM GSCs. Further, we provide novel evidence that the demethylating agent 5-Azacitidine (5-Aza) reactivates TUSC3 expression in MGMT-M GSCs, whereas the combination of 5-Aza and MGMT inhibitor Lomeguatrib is necessary for TUSC3 reactivation in MGMT-UM GSCs. Lastly, we propose a pharmacological epigenetic reactivation strategy involving TUSC3 that leads to significantly prolonged survival in MGMT-M and MGMT-UM orthotopic GSCs models. Collectively, our findings provide a framework and rationale to further explore TUSC3-mediated epigenetic reprogramming strategies that could enhance TMZ sensitivity and outcomes in GBM. Mechanistic and translational evidence gained from such studies could contribute towards optimal design of impactful trials for MGMT-UM GBMs that currently do not have good treatment options.
2024-11-26 | GSE282886 | GEO
Project description:Bromodomain and extra-terminal tail (BET) proteins have been identified as potential epigenetic targets in cancer, including glioblastoma. These epigenetic modifiers link the histone code to gene transcription that can be disrupted with small molecule BET inhibitors (BETi). With the aim of developing rational combination treatments for glioblastoma, we analyzed BETi-induced differential gene expression in glioblastoma derived-spheres, and identified 6 distinct response patterns. To uncover emerging actionable vulnerabilities that can be targeted with a second drug, we extracted the 169 significantly disturbed DNA Damage Response genes and inspected their response pattern. The most prominent candidate with consistent downregulation, was the O-6-methylguanine-DNA methyltransferase (MGMT) gene, a known resistance factor for alkylating agent therapy in glioblastoma. BETi not only reduced MGMT expression in GBM cells, but also inhibited its induction, typically observed upon temozolomide treatment. To determine the potential clinical relevance, we evaluated the specificity of the effect on MGMT expression and MGMT mediated treatment resistance to temozolomide. BETi-mediated attenuation of MGMT expression was associated with reduction of BRD4- and Pol II-binding at the MGMT promoter. On the functional level, we demonstrated that ectopic expression of MGMT under an unrelated promoter was not affected by BETi, while under the same conditions, pharmacologic inhibition of MGMT restored the sensitivity to temozolomide, reflected in an increased level of γ-H2AX, a proxy for DNA double-strand breaks. Importantly, expression of MSH6 and MSH2, which are required for sensitivity to unrepaired O6-methylguanine-lesions, was only briefly affected by BETi. Taken together, the addition of BET-inhibitors to the current standard of care, comprising temozolomide treatment, may sensitize the 50% of patients whose glioblastoma exert an unmethylated MGMT promoter.
| S-EPMC9747918 | biostudies-literature
Project description:Epigenetic Activation of TUSC3 Sensitizes Glioblastoma to Temozolomide Independent of MGMT Promoter Methylation Status
| PRJNA1190943 | ENA
Project description:Acquired resistance of temozolomide (TMZ) is one of the major obstacle of glioblastoma clinical treatment and the mechanism of TMZ resistance is still not very clear. In the presented research we show that deletion of rs16906252-associated MGMT enhancer in MGMT negative glioma cells induced increase sensitivity to temozolomide and combination of RNA-seq and Capture HiC identified several long-range target genes of rs16906252-associated MGMT enhancer. In addition, HiC data shows alterations of chromatin structures in glioma cells survived from high-dosage TMZ treatment and changes of TADs influence rs16906252-associated MGMT enhancer’s long-range regulations of target genes. Our study suggests rs16906252-associated MGMT enhancer regulates glioma cells’ TMZ sensitivity by long-range regulations of several target genes, which is a novel mechanism of regulation of TMZ sensitivity in glioma cells.
2020-04-02 | GSE129476 | GEO
Project description:Patients diagnosed with glioblastoma (GBM) with sustained synthesis of the DNA repair enzyme, O6-methyl guanine DNA methytransferase (MGMT), are rendered resistant to Temozolomide (TMZ) chemotherapy. Here, we hypothesized that pretreatment with the proteasome inhibitor Bortezomib (BTZ, Velcade) might sensitize these GBM to TMZ by depleting MGMT.
2019-08-20 | PXD007193 | Pride
Project description:Temozolomide (TMZ) has been used for the treatment of glioblastoma (GBM) since last decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that a novel enhancer, located between the promoters of Ki67 and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines as well as in recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to reduced levels of MGMT and Ki67, increased TMZ sensitivity and impaired proliferation. Together, these studies uncover a novel mechanism that regulates MGMT expression, confers TMZ resistance and potentially regulates tumor proliferation.
2018-07-13 | GSE113816 | GEO
Project description:An upfront-intensified treatment combining all the three active cytotoxic agents in metastatic colorectal cancer (mCRC) including fluoropyrimidines, oxaliplatin, irinotecan (FOLFOXIRI) plus antiangiogenic blockade with bevacizumab significantly improved survival. No biomarkers are available for predicting sensitivity/resistance to single chemotherapeutic drugs, the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs.
Temozolomide has modest but non-negligible activity (about 10%) in chemo-refractory patients with MGMT methylated mCRC. The response rate to temozolomide-based therapy in pretreated patients is increased to up to 20% when restricting the focus on those with MGMT IHC-negative/MGMT methylated and MSS cancers. Clinical and preclinical synergy has been reported for combination of temozolomide with irinotecan and fluoropyrimidines. Temozolomide could be regarded as a "targeted" chemotherapy for patients with MSS and MGMT silenced tumors. In this subgroup of patients, an intensified triplet upfront regimen including temozolomide, fluoropyrimidines, irinotecan, associated with bevacizumab, could be a novel combination in molecularly super-selected mCRC patients.
Moving from this, the investigators designed this open-label, monocentric, phase 1b study evaluating the safety of the combination regimen 5-fluorouracil, leucovorin, irinotecan, temozolomide and bevacizumab in patients with MGMT silenced and MSS mCRC.
The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced, MSS mCRC. A 3 + 3 design will be used to assess the maximum tolerated dose (MTD) or maximum tested dose of the combination FLIRT-bevacizumab.
| 2362355 | ecrin-mdr-crc
Project description:A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma
| PRJNA454033 | ENA
Project description:STC1 promotes temozolomide resistance of glioblastoma through STAT3-mediated regulation of MGMT.
| PRJNA1088418 | ENA