CircMETTL3, Upregulated in a m6A-dependent Manner, Promotes Breast Cancer Progression through circMETTL3/miR-31-5p/CDK1 axis

Abstract

Background: Growing evidence indicates N6-methyladenosine (m6A) has biological function in oncogenesis. METTL3, the catalytic component, is the most important part of methyltransferase complex and plays a crucial role in cancers. However, the biological function of circRNAs derived from METTL3 and the underlying molecular mechanism remains unclear.Methods: Quantitative real-time PCR was used to determine the circMETTL3 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of circMETTL3 on tumor growth and metastasis in breast cancer. Mechanistically, fluorescent in situ hybridization, dual luciferase reporter assay, RNA pull-down and RNA immunoprecipitation experiments were performed to confirm the interaction between circMETTL3 and miR-31-5p in breast cancer. Furthermore, we explored regulatory effects of m6A modification on circMETTL3 expression with m6A RNA immunoprecipitation.Results: We found that circMETTL3 was significantly upregulated in breast cancer. The results indicated that circMETTL3 could promote breast cancer cell proliferation, migration and invasion as well as tumorigenesis in vivo. Mechanistic analysis showed that circMETTL3 might act as a ceRNA (competing endogenous RNA) of miR-31-5p to relieve the repressive effect of miR-31-5p on its target cyclin-dependent kinases (CDK1). Moreover, m6A modification of circMETTL3 might affect its expression.Conclusion: Our findings suggest that circMETTL3 promotes breast cancer progression through circMETTL3/miR-31-5p/CDK1 axis. Moreover, METTL3, the host gene of circMETTL3, may regulates circMETTL3 expression in a m6A-dependent manner, while circMETTL3 has no effect on METTL3 expression, providing a new relationship between the circRNA and the corresponding host gene. Thus, it may serve as a new diagnostic marker or therapeutic target for breast cancer patients.