The Role of m6A Regulator-Mediated Methylation Modification and Tumor Microenvironment Infiltration in Glioblastoma Multiforme.

Liang Wang,Haiyan Cao,Ying Zhong,Fan Chen,Peigang Ji

doi:10.3389/fcell.2022.842835

Abstract

N6-methyladenosine (m6A) RNA methylation is an emerging epigenetic modification in recent years and epigenetic regulation of the immune response has been demonstrated, but the potential role of m6A modification in GBM tumor microenvironment (TME) cell infiltration and stemness remain unknown. The m6A modification patterns of 310 GBM samples were comprehensively evaluated based on 21 m6A regulators, and we systematically correlated these modification patterns with TME cell infiltration characteristics and stemness characteristics. Construction of m6Ascore to quantify the m6A modification patterns of individual GBM samples using a principal component analysis algorithm. We identified two distinct patterns of m6A modification. The infiltration characteristics of TME cells in these two patterns were highly consistent with the immunophenotype of the GBM, including the immune activation differentiation pattern and the immune desert dedifferentiation pattern. We also identified two modes of regulation of immunity and stemness by m6A methylation. Stromal activation and lack of effective immune infiltration were observed in the high m6Ascore subtype. Pan-cancer analysis results illustrate a significant correlation between m6AScore and tumor clinical outcome, immune infiltration, and stemness. Our work reveals that m6A modifications play an important role in the development of TME and stemness diversity and complexity. Patients with a low m6AScore showed significant therapeutic advantages and clinical benefits. Assessing the m6A modification pattern of individual tumors will help enhance our knowledge of TME infiltration and stemness characteristics, contribute to the development of immunotherapeutic strategies.

Highlights

In recent years, researchers have identified many novel RNA modifications, including 5methylcytosine, N1-methyladenosine and N6-methyladenosine (m6A) (Roundtree et al, 2017) The most prominent example is m6A, which is considered to be the most frequent, common and conserved internal modification in eukaryotic cells (Zhang et al, 2020). m6A is involved in regulating gene expression by affecting transcriptional stability (Geula et al, 2015), processing (Ma et al, 2017), splicing (Dominissini et al, 2012), cap-independent translation and translation efficiency (BoccalettoThe m6A Regulators in Glioblastoma multiforme (GBM) et al, 2018), in addition to promoting cRNA translation (Roignant and Soller, 2017)
We summarize the dynamic reversible process of these m6A RNA methylations mediated by m6A regulators (Ms), including the identification, addition and removal of m6A modification sites, and their biological functions on RNA (Figure 1A)
We evaluated the association between the Ms and the clinical molecular phenotype of GBM, and Figure 1B revealed that the methylation levels of Ms were different between GBM and normal tissues

Summary

Introduction

Researchers have identified many novel RNA modifications, including 5methylcytosine, N1-methyladenosine and N6-methyladenosine (m6A) (Roundtree et al, 2017) The most prominent example is m6A, which is considered to be the most frequent, common and conserved internal modification in eukaryotic cells (Zhang et al, 2020). m6A is involved in regulating gene expression by affecting transcriptional stability (Geula et al, 2015), processing (Ma et al, 2017), splicing (Dominissini et al, 2012), cap-independent translation and translation efficiency (BoccalettoThe m6A Regulators in GBM et al, 2018), in addition to promoting cRNA translation (Roignant and Soller, 2017). The m6A modification is a dynamic and reversible process whose function is regulated by binding proteins, demethylases and methyltransferases, namely the readers, erasers and writers of m6A (Yang et al, 2018). M6A modifications have been shown to potentially affect the formation of a variety of peripheral tumor microenvironments (TME), be involved in cancer stem cells (CSCs) generation and maintenance, the control of cancer progression, and treatment resistance (Ma and Ji, 2020). Previous studies have confirmed that GBM is more heterogeneous than other peripheral tumors, suggesting that multiple factors may influence developmental plasticity and immune checkpoint blockade therapy in GBM, possibly including the TME, RNA modifications, and stem cell phenotype (Malta et al, 2019)

Results

Discussion

Conclusion