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Published on: January 12, 2020
FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2
Meige Sun1, Xiaocui Zhang1, Fangfang Bi1
1Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Abstract:
Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial-mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3' UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC.
Insights
Fat mass and obesity-associated protein (FTO) inhibits epithelial ovarian cancer (EOC) progression by reducing SNAI1 mRNA stability. This FTO-IGF2BP2-SNAI1 pathway offers a potential therapeutic target for EOC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Fat mass and obesity-associated protein (FTO) plays a role in various diseases, including cancers.
- The specific function of FTO in epithelial ovarian cancer (EOC) pathogenesis and its target genes are not fully understood.
Purpose of the Study:
- To elucidate the functional role of FTO in EOC development.
- To investigate the molecular mechanisms by which FTO influences EOC progression.
- To identify potential therapeutic targets within the FTO regulatory network in EOC.
Main Methods:
- In vitro and in vivo functional assays to assess FTO's biological functions.
- m6A RNA immunoprecipitation (MeRIP) and RIP experiments to confirm m6A modification and binding sites.
- Actinomycin D assay to determine RNA stability.
Main Results:
- FTO expression was found to be downregulated in EOC, correlating with increased m6A levels and higher FIGO stages.
- FTO reduced the m6A modification and stability of SNAI1 mRNA, leading to SNAI1 downregulation and inhibition of epithelial-mesenchymal transition (EMT).
- IGF2BP2 was identified as an m6A reader that binds to SNAI1 mRNA, promoting its stability in an FTO-dependent manner.
Conclusions:
- FTO inhibits EOC cell growth and metastasis by downregulating SNAI1 expression via an m6A-IGF2BP2-dependent mechanism.
- The FTO-IGF2BP2-SNAI1 axis represents a promising therapeutic strategy for epithelial ovarian cancer.
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