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Updated: Jun 14, 2025
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
Identification of DNA methylation-regulated WEE1 with potential implications in prognosis and immunotherapy for
Wang-Jing Zhong1,1, Li-Zhen Zhang2,1, Feng Yue3
1Laboratory Center, Huizhou Third People's Hospital, Affiliated Hospital of Guangzhou Medical University, Huizhou, China.
Background:
WEE1 is a critical kinase in the DNA damage response pathway and has been shown to be effective in treating serous uterine cancer. However, its role in gliomas, specifically low-grade glioma (LGG), remains unclear. The impact of DNA methylation on WEE1 expression and its correlation with the immune landscape in gliomas also need further investigation.
Methods:
This study used data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) and utilized various bioinformatics tools to analyze gene expression, survival, gene correlation, immune score, immune infiltration, genomic alterations, tumor mutation burden, microsatellite instability, clinical characteristics of glioma patients, WEE1 DNA methylation, prognostic analysis, single-cell gene expression distribution in glioma tissue samples, and immunotherapy response prediction based on WEE1 expression.
Results:
WEE1 was upregulated in LGG and glioblastoma (GBM), but it had a more significant prognostic impact in LGG compared to other cancers. High WEE1 expression was associated with poorer prognosis in LGG, particularly when combined with wild-type IDH. The WEE1 inhibitor MK-1775 effectively inhibited the proliferation and migration of LGG cell lines, which were more sensitive to WEE1 inhibition. DNA methylation negatively regulated WEE1, and high DNA hypermethylation of WEE1 was associated with better prognosis in LGG than in GBM. Combining WEE1 inhibition and DNA methyltransferase inhibition showed a synergistic effect. Additionally, downregulation of WEE1 had favorable predictive value in immunotherapy response. Co-expression network analysis identified key genes involved in WEE1-mediated regulation of immune landscape, differentiation, and metastasis in LGG.
Conclusion:
Our study shows that WEE1 is a promising indicator for targeted therapy and prognosis evaluation. Notably, significant differences were observed in the role of WEE1 between LGG and GBM. Further investigation into WEE1 inhibition, either in combination with DNA methyltransferase inhibition or immunotherapy, is warranted in the context of LGG.
Insights
WEE1 kinase is upregulated in low-grade glioma (LGG) and linked to poorer prognosis, suggesting it as a therapeutic target. Combining WEE1 inhibition with other treatments may improve outcomes in LGG.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- WEE1 kinase is crucial for DNA damage response and effective in serous uterine cancer.
- The role of WEE1 in gliomas, particularly low-grade glioma (LGG), and its relationship with DNA methylation and the immune landscape require further clarification.
Purpose of the Study:
- To investigate the role of WEE1 in glioma, focusing on its expression, prognostic significance, and potential as a therapeutic target.
- To explore the influence of DNA methylation on WEE1 expression and its correlation with the immune microenvironment in gliomas.
Main Methods:
- Utilized TCGA, CGGA, and GEO datasets for comprehensive bioinformatics analysis.
- Analyzed gene expression, survival data, DNA methylation, immune infiltration, and genomic alterations in glioma patients.
Main Results:
- WEE1 is upregulated in both LGG and glioblastoma (GBM), with a more pronounced prognostic impact in LGG, especially with wild-type IDH.
- High WEE1 expression correlates with poorer prognosis in LGG; WEE1 inhibition shows efficacy against LGG cell lines.
- DNA hypermethylation of WEE1 is associated with better prognosis in LGG than GBM, and combined WEE1 and DNA methyltransferase inhibition demonstrates synergistic effects.
- Downregulation of WEE1 predicts favorable immunotherapy response, and WEE1 co-expression networks reveal key regulatory genes in LGG.
Conclusions:
- WEE1 serves as a potential biomarker for targeted therapy and prognosis in gliomas, with distinct roles in LGG versus GBM.
- Further research into WEE1 inhibition, potentially combined with DNA methyltransferase inhibition or immunotherapy, is recommended for LGG treatment.
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