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Foxo3a-Mediated DNMT3B Impedes Cervical Cancer Cell Proliferation and Migration Capacities through Suppressing PTEN
Hongying Li1, Yuqin Yuan2, Hong Dong1
1Department of Gynecology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
Objective:
Cervical cancer is linked with the constitutive activation of growth factors and gene mutations-induced pro-survival signaling pathways. Herein, we purposed to explore the possible molecular mechanism of Foxo3a-mediated DNMT3B in the proliferation and migration of cervical cancer cells via mediating the PTEN promoter methylation.
Methods:
Foxo3a expression in cervical cancer was tested by qRT-PCR and western blot experiments. The cervical cancer cell biological functions with overexpression of Foxo3a were evaluated by CCK-8 assay, Transwell experiment, and flow cytometry, respectively. MS-PCR was utilized for testing the PTEN methylation levels, and ChIP experiment was implemented for evaluating the enrichment of DNMT3B in the PTEN promoter region and the binding of Foxo3a and DNMT3B. The PTEN methylation and interference with Foxo3a expression were performed in cervical cancer cells, and then their impacts on cervical cancer cell biological functions were observed.
Results:
FOXO3a was expressed at a low level in cervical cancer, and its overexpression contributed to a reduction in cell proliferative, migratory and invasive capabilities, and an elevation in apoptosis rate. Foxo3a blocked its methylation with the PTEN promoter by repressing DNMT3B activity. Upon treatment with methyltransferase inhibitor (5-aza-dc), the malignant phenotypes of cervical cancer cells were diminished. 5-aza-dc neutralized the impacts of silencing Foxo3a on malignant phenotypes.
Conclusion:
This research underlines that Foxo3a blocks its methylation with the PTEN promoter by inhibiting DNMT3B activity, which subsequently impedes cervical cancer cell progression.
Insights
Forkhead box O3a (Foxo3a) suppresses cervical cancer progression by inhibiting DNA methyltransferase 3B (DNMT3B) activity, thereby blocking PTEN promoter methylation. This mechanism reduces cancer cell proliferation and migration.
Area of Science:
- Molecular Oncology
- Epigenetics
- Cell Biology
Background:
- Cervical cancer is characterized by activated growth factors and pro-survival signaling pathways due to gene mutations.
- Understanding the molecular mechanisms driving cervical cancer proliferation and migration is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the molecular mechanism of Forkhead box O3a (Foxo3a)-mediated DNA methyltransferase 3B (DNMT3B) in cervical cancer.
- To explore how Foxo3a influences PTEN promoter methylation, affecting cervical cancer cell proliferation and migration.
Main Methods:
- Quantitative real-time PCR (qRT-PCR) and Western blot assays were used to assess Foxo3a expression.
- Cell proliferation, migration, invasion, and apoptosis were evaluated using CCK-8, Transwell, and flow cytometry assays.
- Methylation-specific PCR (MS-PCR) and Chromatin immunoprecipitation (ChIP) assays were employed to analyze PTEN methylation and DNMT3B/Foxo3a binding.
Main Results:
- Low Foxo3a expression was observed in cervical cancer tissues; its overexpression reduced proliferation, migration, and invasion while increasing apoptosis.
- Foxo3a inhibited PTEN promoter methylation by repressing DNMT3B activity.
- Treatment with a methyltransferase inhibitor (5-aza-dc) diminished malignant phenotypes and counteracted the effects of Foxo3a silencing.
Conclusions:
- Foxo3a inhibits cervical cancer progression by blocking PTEN promoter methylation through the repression of DNMT3B activity.
- These findings highlight a novel epigenetic regulatory mechanism involving Foxo3a and DNMT3B in cervical cancer pathogenesis.
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