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

Jia Shi,Jun Dong,Shan Cheng,Haoran Li,Liping Wang,Suwen Li,Gang Chen,Xuchen Dong,Jiaqi Yuan,Zhiyuan Qian,Yongdong Li

doi:10.3389/fonc.2021.702983

Abstract

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.

Highlights

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]
We demonstrated that methyltransferase-like 3 protein (METTL3) acts as a critical promoter of TMZ resistance in glioma
Elevated METTL3 levels have been associated with malignant characteristics of cancer cells [21], but its role in TMZ resistance in GBM has not been fully understood

Summary

Introduction

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]. 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]. TMZ-resistant cell lines highly expressed O6methylguanine-DNA methyltransferase (MGMT) and alkylpurine–DNA–N-glycosylase (ANPG) [12, 13]. TMZ methylated 12 kinds of DNA bases at different sites, of which, O6-meG was considered the most toxic lesion [14]. MGMT repairs O6-meG through a suicidal response, thereby becoming resistant to TMZ. ANPG repairs the cytotoxic lesions N3methyladenine and N7-methylguanine and contributes to TMZ resistance [12]. The clinical treatment of this deadly tumor urgently requires a more comprehensive understanding of its progression, mechanisms of resistance, and new therapeutic targets

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