A novel compound EPIC-0412 reverses temozolomide resistance via inhibiting DNA repair/MGMT in glioblastoma

Zhao, Jingjie; Yang, Shixue; Cui, Xiaoteng; Wang, Qixue; Yang, Eryan; Tong, Fei; Hong, Biao; Xiao, Menglin; Xin, Lei; Cheng, Xu; Tan, Yanli; Kang, Chunsheng

doi:10.1093/neuonc/noac242

Cited by 27 publications

(19 citation statements)

References 30 publications

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“…Next, the study modeled the structure of the protein encoded by the gene locus with the high‐frequency mutation and found that the deletion of the amino acid at position 16 of ARID1A impairs its binding to the SWI/SNF complex's core subunit BRG1, leading to the abnormal function of the complex. Hence, by starting with the SWI/SNF complex's function and searching for its regulated transcription factors, certain findings substantiated that the E2F family proteins in gliomas play a pivotal role in DNA damage repair and sustaining cell survival, leading to TMZ (temozolomide) resistance 23 . Our results affirmed a correlation between its expression and ARID1A.…”

Section: Discussionsupporting

confidence: 67%

Deep‐targeted gene sequencing reveals ARID1A mutation as an important driver of glioblastoma

Xiao,

Cui,

et al. 2024

CNS Neurosci Ther

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AimsTo investigate the key factors influencing glioma progression and the emergence of treatment resistance by examining the intrinsic connection between mutations in DNA damage and repair‐related genes and the development of chemoresistance in gliomas.MethodsWe conducted a comprehensive analysis of deep‐targeted gene sequencing data from 228 glioma samples. This involved identifying differentially mutated genes across various glioma grades, assessing their functions, and employing I‐TASSER for homology modeling. We elucidated the functional changes induced by high‐frequency site mutations in these genes and investigated their impact on glioma progression.ResultsThe analysis of sequencing mutation results of deep targeted genes in integration revealed that ARID1A gene mutation occurs frequently in glioblastoma and alteration of ARID1A could affect the tolerance of glioma cells to temozolomide treatment. The deletion of proline at position 16 in the ARID1A protein affected the stability of binding of the SWI/SNF core subunit BRG1, which in turn affected the stability of the SWI/SNF complex and led to altered histone modifications in the CDKN1A promoter region, thereby affecting the biological activity of glioma cells, as inferred from modeling and protein interaction analysis.ConclusionThe ARID1A gene is a critical predictive biomarker for glioma. Mutations at the ARID1A locus alter the stability of the SWI/SNF complex, leading to changes in transcriptional regulation in glioma cells. This contributes to an increased malignant phenotype of GBM and plays a pivotal role in mediating chemoresistance.

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Section: Discussionsupporting

confidence: 67%

Deep‐targeted gene sequencing reveals ARID1A mutation as an important driver of glioblastoma

Xiao,

Cui,

et al. 2024

CNS Neurosci Ther

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“…The specialized regulation of DNA methylation damage repair pathway is the most useful application to improve TMZ treatment efficiency. Previously, some studies uncover that several mechanisms of MGMT inhibitors have been developed sensitizing cells to TMZ 16,17 . However, we are still unsatisfied with those inhibitors which are less effective, with more side effects and non‐specific targets.…”

Section: Discussionmentioning

confidence: 99%

USP19 regulates DNA methylation damage repair and confers temozolomide resistance through MGMT stabilization

Liu,

Wang,

Zhu

et al. 2024

CNS Neurosci Ther

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ObjectiveTo elucidate the relationship between USP19 and O(6)‐methylguanine‐DNA methyltransferase (MGMT) after temozolomide treatment in glioblastoma (GBM) patients with chemotherapy resistance.MethodsScreening the deubiquitinase pannel and identifying the deubiquitinase directly interacts with and deubiquitination MGMT. Deubiquitination assay to confirm USP19 deubiquitinates MGMT. The colony formation and tumor growth study in xenograft assess USP19 affects the GBM sensitive to TMZ was performed by T98G, LN18, U251, and U87 cell lines. Immunohistochemistry staining and survival analysis were performed to explore how USP19 is correlated to MGMT in GBM clinical management.ResultsUSP19 removes the ubiquitination of MGMT to facilitate the DNA methylation damage repair. Depletion of USP19 results in the glioblastoma cell sensitivity to temozolomide, which can be rescued by overexpressing MGMT. USP19 is overexpressed in glioblastoma patient samples, which positively correlates with the level of MGMT protein and poor prognosis in these patients.ConclusionThe regulation of MGMT ubiquitination by USP19 plays a critical role in DNA methylation damage repair and GBM patients’ temozolomide chemotherapy response.

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“…As a well-known transcription factor, E2F1 regulates various DDR-related genes 47 . We previously reported that RAD51AP1 is a potential mediator of EGFRvIII and an oncogene in GBM 32 .…”

Section: Discussionmentioning

confidence: 99%

Identification of the E2F1-RAD51AP1 axis as a key factor in MGMT-methylated GBM TMZ resistance

et al. 2023

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Objective: Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively-activated mutation of EGFR that contributes to the malignant progression of glioblastoma multiforme (GBM). Temozolomide (TMZ) is a standard chemotherapeutic for GBM, but TMZ treatment benefits are compromised by chemoresistance. This study aimed to elucidate the crucial mechanisms leading to EGFRvIII and TMZ resistance. Methods: CRISPR-Cas13a single-cell RNA-seq was performed to thoroughly mine EGFRvIII function in GBM. Western blot, real-time PCR, flow cytometry, and immunofluorescence were used to determine the chemoresistance role of E2F1 and RAD51-associated protein 1 (RAD51AP1). Results: Bioinformatic analysis identified E2F1 as the key transcription factor in EGFRvIII-positive living cells. Bulk RNA-seq analysis revealed that E2F1 is a crucial transcription factor under TMZ treatment. Western blot suggested enhanced expression of E2F1 in EGFRvIII-positive and TMZ-treated glioma cells. Knockdown of E2F1 increased sensitivity to TMZ. Venn diagram profiling showed that RAD51AP1 is positively correlated with E2F1, mediates TMZ resistance, and has a potential E2F1 binding site on the promoter. Knockdown of RAD51AP1 enhanced the sensitivity of TMZ; however, overexpression of RAD51AP1 was not sufficient to cause chemotherapy resistance in glioma cells. Furthermore, RAD51AP1 did not impact TMZ sensitivity in GBM cells with high O6-methylguanine-DNA methyltransferase (MGMT) expression. The level of RAD51AP1 expression correlated with the survival rate in MGMT-methylated, but not MGMT-unmethylated TMZ-treated GBM patients. Conclusions: Our results suggest that E2F1 is a key transcription factor in EGFRvIII-positive glioma cells and quickly responds to TMZ treatment. RAD51AP1 was shown to be upregulated by E2F1 for DNA double strand break repair. Targeting RAD51AP1 could facilitate achieving an ideal therapeutic effect in MGMT-methylated GBM cells.

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A novel compound EPIC-0412 reverses temozolomide resistance via inhibiting DNA repair/MGMT in glioblastoma

Cited by 27 publications

References 30 publications

Deep‐targeted gene sequencing reveals ARID1A mutation as an important driver of glioblastoma

Deep‐targeted gene sequencing reveals ARID1A mutation as an important driver of glioblastoma

USP19 regulates DNA methylation damage repair and confers temozolomide resistance through MGMT stabilization

Identification of the E2F1-RAD51AP1 axis as a key factor in MGMT-methylated GBM TMZ resistance

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