M6A reader IGF2BP2-stabilized CASC9 accelerates glioblastoma aerobic glycolysis by enhancing HK2 mRNA stability

Hongjiang Liu,Jiankai Yang,Shan Qin,Xiaofeng Sun,Xiaopeng Liu,Changqi Liu,Chen Li,Jipeng Yang,Le Jiang,Zhongjie Yan,Shunyao Zhang

doi:10.1038/s41420-021-00674-y

Abstract

N6-methyladenosine (m6A) has been identified to exert critical roles in human cancer; however, the regulation of m6A modification on glioblastoma multiforme (GBM) and long non-coding RNA (lncRNA) CASC9 (cancer susceptibility 9) is still unclear. Firstly, MeRIP-Seq revealed the m6A profile in the GBM. Moreover, the m6A-related lncRNA CASC9 expression was significantly elevated in the GBM tissue and its ectopic high expression was associated with poor survival, acting as an independent prognostic factor for GBM patients. Functionally, the aerobic glycolysis was promoted in the CASC9 overexpression transfection, which was inhibited in CASC9 knockdown in GBM cells. Mechanistically, m6A reader IGF2BP2 (insulin-like growth factor 2 mRNA binding protein 2) could recognize the m6A site of CASC9 and enhance its stability, then CASC9 cooperated with IGF2BP2, forming an IGF2BP2/CASC9 complex, to increase the HK2 (Hexokinase 2) mRNA stability. Our findings reveal that CASC9/IGF2BP2/HK2 axis promotes the aerobic glycolysis of GBM.

Highlights

Glioblastoma multiforme (GBM) is one of the most aggressive tumors of the central nervous system while representing 80% of all malignant brain tumors [1, 2].Since decades GBM is characterized by a median overall survival of 15 months, suggesting the tremendous hazard of GBM [3, 4]. GBM is very dangerous, it is hardly excised by surgical treatment or intensive treatments, leading to a low survival rate [5]
M6A demethylase ALKBH5 is highly expressed in GBM stem-like cells and ALKBH5 mediated the demethylation of FOXM1 nascent transcripts
CASC9/IGF2BP2 complex contributed to the stability of hexokinase 2 (HK2) mRNA In the correlation analysis, we found that the expression of IGF2BP2 was positively correlated to the expression of HK2 in the GBM group (Fig. 5A) based on the public database data (GEPIA, analysis found that the overexpression of CASC9 could enhance http://gepia.cancer-pku.cn/)

Summary

Introduction

Glioblastoma multiforme (GBM) is one of the most aggressive tumors of the central nervous system while representing 80% of all malignant brain tumors [1, 2].Since decades GBM is characterized by a median overall survival of 15 months, suggesting the tremendous hazard of GBM [3, 4]. GBM is very dangerous, it is hardly excised by surgical treatment or intensive treatments, leading to a low survival rate [5]. Since decades GBM is characterized by a median overall survival of 15 months, suggesting the tremendous hazard of GBM [3, 4]. GBM is characterized by a median overall survival around. 15 months for decades, suggesting an urgent need for an accurate underlying mechanism of GBM. N6-methyladenosine (m6A) is the most abundant modification in mRNA mediated by m6A methyltransferases, demethylases and readers [6]. M6A methyltransferases install the m6A modification on RNA, especially methyltransferase-like (METTL3) and its auxiliary partners METTL14 and WTAP. M6A modification is found to be involved in most pivotal biological processes, including stem cells differentiation, spermatogenesis, RNA metabolism and so on. M6A demethylase ALKBH5 is highly expressed in GBM stem-like cells and ALKBH5 mediated the demethylation of FOXM1 nascent transcripts.

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Conclusion