DNMT1 promotes bladder cancer progression and immune escape by inhibiting MYH11 expression by methylating its
Shan Gao1, Tianyi Liu1, Qing Liu2
1Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Harbin, 150001, Heilongjiang, People's Republic of China.
Background:
Bladder cancer (BC) is a fatal malignancy of the urinary tract with limited effective biomarkers and therapeutic targets. This paper delved into the mechanism of MYH11 and DNMT1 in BC progression.
Methods:
Differential genes obtained from the GSE3167 dataset were analyzed by the R language limma package. RT-qPCR, Western blot, and immunohistochemistry were carried out to assess MYH11 and DNMT1 expression in BC cell lines and BC tissues. Cell migration, invasion, proliferation, and apoptosis were detected by Transwell assay, CCK-8, and TUNEL after different lentiviral vector treatments. MB49 cells with different infections were administered into mice to monitor tumor growth and immune escape. Flow cytometry detected the rate of CD45+CD4+-positive cells in the tumor tissues and PD-1 and TIM-3 expression in CD4+ T cells. MYH11 methylation was analyzed using the qMSP assay. ChIP and dual-luciferase assay were used for regulatory assays.
Results:
MYH11 was lowly expressed in BC. Overexpression of MYH11 inhibited the malignant progression of BC cells, promoted anti-tumor immune responses of CD4+ T cells, and inhibited immune escape and tumor development in mice. DNMT1 inhibited MYH11 expression by elevating MYH11 promoter methylation. DNMT1 inhibition impeded the immune escape of BC cells, which was reversed by silencing MYH11. DNMT1 silencing prevented immune escape via transcriptional activation of MYH11 and hindered tumor growth in mice.
Conclusion:
DNMT1 promotes immune escape and malignant progression of BC by methylating the promoter of MYH11.
Insights
DNA methyltransferase 1 (DNMT1) promotes bladder cancer (BC) progression and immune escape by methylating the MYH11 gene promoter. MYH11 overexpression inhibits BC progression and enhances anti-tumor immunity.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Bladder cancer (BC) is a lethal malignancy with few effective biomarkers and therapeutic targets.
- Understanding the molecular mechanisms driving BC progression and immune evasion is critical.
- This study investigates the roles of MYH11 and DNA methyltransferase 1 (DNMT1) in BC.
Purpose of the Study:
- To elucidate the mechanism by which MYH11 and DNMT1 influence bladder cancer progression.
- To determine the impact of MYH11 and DNMT1 on anti-tumor immunity and immune escape in BC.
- To explore potential therapeutic strategies targeting the MYH11-DNMT1 axis in BC.
Main Methods:
- Bioinformatic analysis of the GSE3167 dataset.
- Quantitative real-time PCR (RT-qPCR), Western blot, and immunohistochemistry for gene expression.
- In vitro assays (Transwell, CCK-8, TUNEL) for cell behavior and apoptosis.
- In vivo mouse models for tumor growth and immune escape.
- Flow cytometry for immune cell profiling and checkpoint molecule analysis.
- Quantitative methylation-specific PCR (qMSP), Chromatin immunoprecipitation (ChIP), and dual-luciferase assays for epigenetic regulation.
Main Results:
- MYH11 expression was significantly downregulated in bladder cancer.
- Overexpression of MYH11 suppressed BC cell proliferation, migration, and invasion, while promoting CD4+ T cell anti-tumor responses.
- DNMT1 inhibited MYH11 expression via promoter methylation, contributing to BC immune escape and tumor development.
- DNMT1 inhibition reversed immune escape, which was dependent on MYH11 transcriptional activation.
Conclusions:
- DNMT1 promotes bladder cancer progression and immune escape by epigenetically silencing MYH11.
- MYH11 acts as a tumor suppressor by enhancing anti-tumor immunity and inhibiting immune escape.
- Targeting the DNMT1-MYH11 pathway may offer a novel therapeutic strategy for bladder cancer.
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