Background Despite the development of new treatment protocols for glioblastoma (GBM), temozolomide (TMZ) resistance remains a primary hindrance. Previous studies, including our study, have shown that aberrant N6‐methyladenosine (m 6 A) modification is implicated in GBM pathobiology. However, the roles and precise mechanisms of m 6 A modification in the regulation of TMZ resistance in GBM remain unclear. Methods m 6 A individual‐nucleotide‐resolution cross‐linking and immunoprecipitation sequencing (miCLIP‐seq) was performed to identify m 6 A modification of transcripts in TMZ‐resistant and ‐sensitive tumors. To explore the role of METTL3 in TMZ resistance, TMZ‐resistant GBM cells were transfected with METTL3 shRNA or overexpression lentivirus and then assessed by cell viability, tumor sphere formation, and apoptosis assays. An intracranial GBM xenograft model was developed to verify the effect of METTL3 depletion during TMZ treatment in vivo. ATAC‐seq, ChIP‐qPCR, and dual‐luciferase reporter assays were carried out to verify the role of SOX4/EZH2 in the modulation of METTL3 expression upon TMZ treatment. Results We demonstrated that TMZ treatment upregulated the expression of the m 6 A methyltransferase METTL3, thereby increasing m 6 A modification of histone modification‐related gene transcripts. METTL3 is required to maintain the features of GBM stem cells. When combined with TMZ, METTL3 silencing suppressed orthotopic TMZ‐resistant xenograft growth in a cooperative manner. Mechanistically, TMZ induced a SOX4‐mediated increase in chromatin accessibility at the METTL3 locus by promoting H3K27ac levels and recruiting RNA polymerase II. Moreover, METTL3 depletion affected the deposition of m 6 A on histone modification‐related gene transcripts, such as EZH2, leading to nonsense‐mediated mRNA decay. We revealed an important role of EZH2 in the regulation of METTL3 expression, which was via an H3K27me3 modification‐independent manner. Conclusions Our findings uncover the fundamental mechanisms underlying the interplay of m 6 A RNA modification and histone modification in TMZ resistance and emphasize the therapeutic potential of targeting the SOX4/EZH2/METTL3 axis in the treatment of TMZ‐resistant GBM.

Glioblastoma (GBM) is a group of intracranial neoplasms with intra-tumoral heterogeneity. RNA N6-methyladenosine (m6A) methylation modification reportedly plays roles in immune response. The relationship between the m6A modification pattern and immune cell infiltration in GBM remains unknown. Utilizing expression data of GBM patients, we thoroughly explored the potential m6A modification pattern and m6A-related signatures based on 21 regulators. Thereafter, the m6A methylation modification-based prognostic assessment pipeline (MPAP) was constructed to quantitatively assess GBM patients’ clinical prognosis combining the Robustness and LASSO regression. Single-sample gene-set enrichment analysis (ssGSEA) was used to estimate the specific immune cell infiltration level. We identified two diverse clusters with diverse m6A modification characteristics. Based on differentially expressed genes (DEGs) within two clusters, m6A-related signatures were identified to establish the MPAP, which can be used to quantitatively forecast the prognosis of GBM patients. In addition, the relationship between 21 m6A regulators and specific immune cell infiltration was demonstrated in our study and the m6A regulator ELAVL1 was determined to play an important role in the anticancer response to PD-L1 therapy. Our findings indicated the relationship between m6A methylation modification patterns and tumor microenvironment immune cell infiltration, through which we could comprehensively understand resistance to multiple therapies in GBM, as well as accomplish precise risk stratification according to m6A-related signatures.

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Imbalance in copper homeostasis can be lethal to the body. A recent study found that excess copper induces cell death in a way that has never been characterized before, which is dependent on mitochondrial stress and referred to as "cuproptosis." The role of cuproptosis in tumors has not yet been elucidated. In this study, we revealed the complex and important roles of cuproptosis regulators and cuproptosis activity in tumors via a comprehensive analysis of multi-omics data from more than 10 000 samples of 33 tumor types. We found that the cyclin-dependent kinase inhibitor 2A is the most frequently altered cuproptosis regulator, and the cuproptosis regulator expression is dysregulated in various tumors. Additionally, we developed a cuproptosis activity score to re ect the overall cuproptosis level. Based on the expression levels of cuproptosis regulators, tumors can be divided into two clusters with different cuproptosis activities and survival outcomes. Importantly, cuproptosis activity was found to be associated with the prognosis of multiple tumors and multiple tumor-related pathways, including fatty acid metabolism and remodeling of the tumor microenvironment. Furthermore, cuproptosis extensively increased the sensitivity to multiple drugs and exhibited potential to predict the outcome of immunotherapy. We also comprehensively identi ed cuproptosis-related microRNAs, long non-coding RNAs, and transcription factors. In summary, this study reveals important molecular and clinical characteristics of cuproptosis regulators and cuproptosis activity in tumors, and suggests the use of cuproptosis as a promising tumor therapeutic approach. This study provides an important reference point for future cuproptosis-related research.

Purpose: Gliomas are the most common primary malignant neoplasms of the central nervous system. Secreted phospholipases A2 (sPLA2s) are known to play an important role in various physiological processes, including bioactive lipid production, defense mechanisms, and cell signaling. However, their roles and clinical importance in gliomas remain unclear. Patients and methods: In this study, we analyzed the association between the expression of various sPLA2-encoding genes and the clinicopathology of gliomas, using the data of 1047 patients obtained from a public database. Immunohistochemical analysis of 82 glioma tissues was also carried out to assess the relationship between phospholipase A2 group V (PLA2G5) protein expression and the World Health Organization (WHO) glioma grades. Results: We found that high PLA2G5 gene expression was associated with unfavorable prognosis in both low-grade and high-grade gliomas. The immunohistochemistry of the 82 glioma tissues further confirmed that PLA2G5 protein expression was dependent on the WHO glioma grade. In addition, we found a correlation between PLA2G5 gene expression and both epithelial–mesenchymal transition and the isocitrate dehydrogenase 1 mutation status in these tumors. Conclusion: Our results indicate that PLA2G5 could be a potential biomarker for predicting poor prognosis in patients with gliomas.