Epigenetic modulator inhibition overcomes temozolomide chemoresistance and antagonizes tumor recurrence of glioblastoma

Moon, Byoung-San; Cai, Mingyang; Lee, Grace; Zhao, Tong; Song, Xiaofeng; Giannotta, Steven L.; Attenello, Frank J.; Yu, Min; Lu, Wange

doi:10.1172/jci127916

Cited by 17 publications

(13 citation statements)

References 50 publications

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“…Many studies have suggested that epigenetic modification plays a crucial role in the pathogenesis of GBM. 20,21 Recently, N6methyladenosine modification has attracted extensive attention, but the specific mechanism of this novel RNA modification in the occurrence and development of GBM has not been fully studied, especially in circRNA. 11 We used RNA N6-methyladenosine sequencing to explore the state of N6-methyladenosine-circRNA modifications in GBM tissues.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of N6‐methyladenosine modification of circRNAs in glioblastoma

Zhang

Geng

et al. 2021

J Cellular Molecular Medi

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This research systematically profiled the global N6‐methyladenosine modification pattern of circular RNAs (circRNAs) in glioblastoma (GBM). Based on RNA methylation sequencing (MeRIP sequencing or N6‐methyladenosine sequencing) and RNA sequencing, we described the N6‐methyladenosine modification status and gene expression of circRNAs in GBM and normal brain tissues. N6‐methyladenosine–related circRNAs were immunoprecipitated and validated by real‐time quantitative PCR. Bioinformatics analysis and related screening were carried out. Compared with those of the NC group, the circRNAs from GBM exhibited 1370 new N6‐methyladenosine peaks and 1322 missing N6‐methyladenosine peaks. Among the loci associated with altered N6‐methyladenosine peaks, 1298 were up‐regulated and 1905 were down‐regulated. The N6‐methyladenosine level tended to be positively correlated with circRNA expression. Bioinformatics analysis was used to predict the biological function of N6‐methyladenosine–modified circRNAs and the corresponding signalling pathways. In addition, through PCR validation combined with clinical data mining, we identified five molecules of interest (BUB1, C1S, DTHD1, F13A1 and NDC80) that could be initial candidates for further study of the function and mechanism of N6‐methyladenosine–mediated GBM development. In conclusion, our findings demonstrated the N6‐methyladenosine modification pattern of circRNAs in human GBM, revealing the possible roles of N6‐methyladenosine–mediated novel noncoding RNAs in the origin and progression of GBM.

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of N6‐methyladenosine modification of circRNAs in glioblastoma

Zhang

Geng

et al. 2021

J Cellular Molecular Medi

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“…Taking into account the relevance of the epigenetic landscape in gliomas and, in particular, in the prediction of treatment sensitivity, in recent years, pharmacological research is increasingly considering the possibility of including epidrugs in therapeutic options for GBM, with particular regard to personalized therapy ( Zang et al, 2018 ; Phillips et al, 2020 ). Several clinical trials are currently evaluating the effect of different epigenetic modulators, including DNA-methyltransferase inhibitors (DNMTi), used alone or in combined therapies with TMZ or radiations ( ClinicalTrials.gov, 2021 ; Wu et al, 2021 ), and various studies have proposed epidrugs and DNMTi, among other, to optimize the use of TMZ for personalized medicine in GBM ( Seelan et al, 2018 ; Yamashita et al, 2019 ; Belter et al, 2020 ; Gallitto et al, 2020 ; Moon et al, 2020 ; Sun and Turcan, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Modified Adenosines Sensitize Glioblastoma Cells to Temozolomide by Affecting DNA Methyltransferases

et al. 2022

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Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor, and due to its unique features, its management is certainly one of the most challenging ones among all cancers. N6-isopentenyladenosine (IPA) and its analog N6-benzyladenosine (N6-BA) are modified nucleosides endowed with potent antitumor activity on different types of human cancers, including GBM. Corroborating our previous finding, we demonstrated that IPA and N6-BA affect GBM cell line proliferation by modulating the expression of the F-box WD repeat domain-containing-7 (FBXW7), a tumor suppressor with a crucial role in the turnover of many proteins, such as SREBPs and Mcl1, involved in malignant progression and chemoresistance. Luciferase assay revealed that IPA-mediated upregulation of FBXW7 translates in transcriptional inactivation of its oncogenic substrates (Myc, NFkB, or HIF-1α). Moreover, downregulating MGMT expression, IPA strongly enhances the killing effect of temozolomide (TMZ), producing a favorable sensitizing effect starting from a concentration range much lower than TMZ EC50. Through DNA methyltransferase (DNMT) activity assay, analysis of the global DNA methylation, and the histone modification profiles, we demonstrated that the modified adenosines behave similar to 5-AZA-dC, known DNMT inhibitor. Overall, our results provide new perspectives for the first time, suggesting the modified adenosines as epigenetic tools able to improve chemo- and radiotherapy efficacy in glioblastoma and potentially other cancers.

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“…PP could attenuate self-renewal and proliferative capacities of glioblastoma-initiating cells (GICs) in part through inhibition of Wnt/β-catenin signaling and other essential stem cell regulatory pathways [ 47 ]. In addition, PP could induce GSC-selective cytotoxicity by inhibiting mitochondrial function [ 48 ] or promoting methyl CpG binding domain protein 3 (MBD3) protein degradation, which plays a critical role in stem cell pluripotency, differentiation, and cell death [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Pyrvinium pamoate regulates MGMT expression through suppressing the Wnt/β-catenin signaling pathway to enhance the glioblastoma sensitivity to temozolomide

Liu

Jin

et al. 2021

Cell Death Discov.

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Temozolomide (TMZ) is the mainstream chemotherapeutic drug for treating glioblastoma multiforme (GBM), but the intrinsic or acquired chemoresistance to TMZ has become the leading clinical concern, which is related to the repair of DNA alkylation sites by O6-methylguanine-DNA methyltransferase (MGMT). Pyrvinium pamoate (PP), the FDA-approved anthelminthic drug, has been reported to inhibit the Wnt/β-catenin pathway within numerous cancer types, and Wnt/β-catenin signaling pathway can modulate the expression of MGMT gene. However, whether PP affects the expression of MGMT and enhances TMZ sensitivity in GBM cells remains unclear. In the present study, we found that PP and TMZ had synergistic effect on inhibiting the viability of GBM cells, and PP induced inhibition of MGMT and enhanced the TMZ chemosensitivity of GBM cells through down-regulating Wnt/β-catenin pathway. Moreover, the overexpression of MGMT or β-catenin weakened the synergy between PP and TMZ. The mechanism of PP in inhibiting the Wnt pathway was indicated that PP resulted in the degradation of β-catenin via the AKT/GSK3β/β-catenin signaling axis. Moreover, Ser552 phosphorylation in β-catenin, which promotes its nuclear accumulation and transcriptional activity, is blocked by PP that also inhibits the Wnt pathway to some extent. The intracranial GBM mouse model also demonstrated that the synergy between PP and TMZ could be achieved through down-regulating β-catenin and MGMT, which prolonged the survival time of tumor-bearing mice. Taken together, our data suggest that PP may serve as the prospect medicine to improve the chemotherapeutic effect on GBM, especially for chemoresistant to TMZ induced by MGMT overexpression.

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Epigenetic modulator inhibition overcomes temozolomide chemoresistance and antagonizes tumor recurrence of glioblastoma

Cited by 17 publications

References 50 publications

Identification and characterization of N6‐methyladenosine modification of circRNAs in glioblastoma

Identification and characterization of N6‐methyladenosine modification of circRNAs in glioblastoma

Modified Adenosines Sensitize Glioblastoma Cells to Temozolomide by Affecting DNA Methyltransferases

Pyrvinium pamoate regulates MGMT expression through suppressing the Wnt/β-catenin signaling pathway to enhance the glioblastoma sensitivity to temozolomide

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