Epigenomic Reprogramming as a Driver of Malignant Glioma

Phillips, Richard E.; Soshnev, Alexey A.; Allis, C. David

doi:10.1016/j.ccell.2020.08.008

Cited by 76 publications

(64 citation statements)

References 165 publications

(196 reference statements)

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“…6,7 Gliomagenesis and tumor development are complicated processes that have yet to be fully elucidated. 8,9 Thus, it is crucial to fully elucidate GBM pathogenesis and identify effective targets for diagnosis and anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Long Non-Coding RNA UBA6-AS1 Promotes the Malignant Properties of Glioblastoma by Competitively Binding to microRNA-760 and Enhancing Homeobox A2 Expression

Cheng

Liu

Zhang

et al. 2021

CMAR

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Background: The dysregulation of long non-coding RNAs is a frequent finding in glioblastoma (GBM) and is considered as a crucial mechanism contributing to GBM oncogenesis and progression. The biological roles and underlying mechanisms of action of UBA6 antisense RNA 1 (UBA6-AS1) in GBM have been rarely investigated. Therefore, the aim of the present study was to investigate in detail the role of UBA6-AS1 in the modulation of the malignant properties of GBM and explore the possible underlying mechanism(s). Methods: The expression of UBA6-AS1 in GBM was determined via reverse transcriptionquantitative PCR. Cell Counting Kit-8 assay, flow cytometric analysis, Transwell migration and invasion assays, and in vivo tumorigenicity assay were applied to elucidate the biological effects of UBA6-AS1 on GBM cells. The possible biological events associated with UBA6-AS1 were investigated by luciferase reporter, RNA immunoprecipitation (RIP) and rescue assays. Results: UBA6-AS1 was overexpressed in GBM, which was consistent with the data from The Cancer Genome Atlas database. In the case of UBA6-AS1 depletion, GBM cell proliferation, migration and invasion were notably decreased and cell apoptosis was enhanced in vitro. Additionally, knockdown of UBA6-AS1 suppressed the proliferation of GBM cells in vivo. Mechanistically, UBA6-AS1 functioned as a competing endogenous RNA by adsorbing miR-760 and, consequently, upregulating homeobox A2 (HOXA2) expression. Rescue experiments demonstrated that the UBA6-AS1 silencing-mediated regulatory effects on GBM cells were reversed by the decrease of miR-760 or restoration of HOXA2 expression. Conclusion: Therefore, the results of the present study revealed that UBA6-AS1 promoted the malignant progression of GBM via targeting the miR-760/HOXA2 axis, thereby representing a promising effective target for the treatment of GBM.

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Section: Introductionmentioning

confidence: 99%

Long Non-Coding RNA UBA6-AS1 Promotes the Malignant Properties of Glioblastoma by Competitively Binding to microRNA-760 and Enhancing Homeobox A2 Expression

Cheng

Liu

Zhang

et al. 2021

CMAR

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“…Despite advances in the development of chemotherapeutic agents, including targeted therapies, the overall survival after diagnosis is usually less than two years (26,27). Recent experimental and clinical studies have shown that epigenetic regulation of GBM also plays an important role in promoting tumorigenesis and the development of drug resistance (2,28,29). m 6 A RNA methylation is an important RNA modification that has been shown to play an important role in the genesis and development of glioblastoma (30).…”

Section: Discussionmentioning

confidence: 99%

“…Owing to the introduction of temozolomide (TMZ), an alkylation agent, and the use of radiotherapy in combination with TMZ adjuvant therapy, the median survival of patients with glioblastoma multiforme (GBM) was increased from 12.1 months to 14.6 months (1)(2)(3)(4)(5). However, the overall clinical efficacy of this regimen remains disappointing, mainly because of inherent or induced resistance to TMZ treatment (6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

METTL3 Promotes the Resistance of Glioma to Temozolomide via Increasing MGMT and ANPG in a m6A Dependent Manner

et al. 2021

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Acquired chemoresistance is a major limiting factor in the clinical treatment of glioblastoma (GBM). However, the mechanism by which GBM acquires therapeutic resistance remains unclear. Here, we aimed to investigate whether METTL3-mediated N6-methyladenosine (m6A) modification contributes to the temozolomide (TMZ) resistance in GBM. We demonstrated that METTL3 METTL3-mediated m6A modification were significantly elevated in TMZ-resistant GBM cells. Functionally, METTL3 overexpression impaired the TMZ-sensitivity of GBM cells. In contrast, METTL3 silencing or DAA-mediated total methylation inhibition improved the sensitivity of TMZ-resistant GBM cells to TMZ in vitro and in vivo. Furthermore, we found that two critical DNA repair genes (MGMT and APNG) were m6A-modified by METTL3, whereas inhibited by METTL3 silencing or DAA-mediated total methylation inhibition, which is crucial for METTL3-improved TMZ resistance in GBM cells. Collectively, METTL3 acts as a critical promoter of TMZ resistance in glioma and extends the current understanding of m6A related signaling, thereby providing new insights into the field of glioma treatment.

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“…Glioma, originated from neuroepithelial tissue, is one of the commonest primary and intractable central nerve system (CNS) malignant tumors with the highest incidence rate, rapidly progressive nature and dismal prognosis ( Phillips et al, 2020 ; Wang et al, 2020 ). Glioblastoma multiforme [GBM, World Health Organization (WHO) grade IV] is a recalcitrant and incurable kind of glioma with the worst prognosis ( Hambardzumyan and Bergers, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

“…Ni Tong 1,2 † , Zhenqiang He 3 † , Yujie Ma 2 † , Zheng Wang 4 , Ziming Huang 2 , Haihong Cao 1,2 , Lanyang Xu 1,2 , Yuheng Zou 1,2 , Wanyu Wang 1,2 , Chenpeng Yi 1,2 , Zhixin Yin 5 and Qirui Wang 1,2 * INTRODUCTION Glioma, originated from neuroepithelial tissue, is one of the commonest primary and intractable central nerve system (CNS) malignant tumors with the highest incidence rate, rapidly progressive nature and dismal prognosis (Phillips et al, 2020;Wang et al, 2020). Glioblastoma multiforme [GBM, World Health Organization (WHO) grade IV] is a recalcitrant and incurable kind of glioma with the worst prognosis (Hambardzumyan and Bergers, 2015).…”

mentioning

confidence: 99%

Tumor Associated Macrophages, as the Dominant Immune Cells, Are an Indispensable Target for Immunologically Cold Tumor—Glioma Therapy?

Tong

et al. 2021

Front. Cell Dev. Biol.

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Tumor microenvironment (TME) is the cornerstone of the occurrence, development, invasion and diffusion of the malignant central nerve system (CNS) tumor, glioma. As the largest number of inflammatory cells in glioma TME, tumor associated macrophages (TAMs) and their secreted factors are indispensable to the progression of glioma, which is a well-known immunologically “cold” tumor, including the growth of tumor cells, invasion, migration, angiogenesis, cancer immunosuppression and metabolism. TAMs intimately interface with the treatment failure and poor prognosis of glioma patients, and their density increases with increasing glioma grade. Recently, great progress has been made in TAM-targeting for anti-tumor therapy. According to TAMs’ function in tumorigenesis and progression, the major anti-tumor treatment strategies targeting TAMs are to hinder macrophage recruitment in TME, reduce TAMs viability or remodel TAMs phenotype from M2 to M1. Different approaches offer unique and effective anti-tumor effect by regulating the phagocytosis, polarization and pro-tumor behaviors of macrophages in the therapy of glioma. The present review summarizes the significant characteristics and related mechanisms of TAMs and addresses the related research progress on targeting TAMs in glioma.

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Epigenomic Reprogramming as a Driver of Malignant Glioma

Cited by 76 publications

References 165 publications

Long Non-Coding RNA UBA6-AS1 Promotes the Malignant Properties of Glioblastoma by Competitively Binding to microRNA-760 and Enhancing Homeobox A2 Expression

Long Non-Coding RNA UBA6-AS1 Promotes the Malignant Properties of Glioblastoma by Competitively Binding to microRNA-760 and Enhancing Homeobox A2 Expression

METTL3 Promotes the Resistance of Glioma to Temozolomide via Increasing MGMT and ANPG in a m6A Dependent Manner

Tumor Associated Macrophages, as the Dominant Immune Cells, Are an Indispensable Target for Immunologically Cold Tumor—Glioma Therapy?

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