CircMETTL6 Suppresses Ovarian Cancer Cell Growth and Metastasis Through Inhibition of GDF15 Transcription by Disrupting the NONO‐POLR2A Complex

Circular RNAs (circRNAs) are a distinctive class of non-coding RNAs with covalent closed-loop structure, lacking 5' caps and 3' poly(A) tails. These molecules are prevalent in eukaryotes and play key roles in cancer. Here, the function of a new circRNA, circMETTL6, in ovarian cancer is identified and investigated. The prognostic significance of circMETTL6 is assessed using RNA in situ hybridization. Functional studies involving circMETTL6 overexpression are performed both in vitro and in vivo. Mechanistic investigations are performed using RNA-seq, RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, chromatin immunoprecipitation, protein degradation assay and dual-luciferase reporter assays. circMETTL6 is significantly downregulated in ovarian cancer, and its lower expression correlates with worse prognosis. Overexpression of circMETTL6 significantly inhibited proliferation, migration, and invasion of ovarian cancer cell in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, circMETTL6 recruited the non-POU domain containing octamer binding protein (NONO) by binding to its Coiled-coil domain and disrupted its binding with RNA polymerase II subunit A (POLR2A), and consequently inhibiting growth differentiation factor 15 (GDF15) transcription, thereby suppressing ovarian cancer progression. These findings establish circMETTL6 as a novel tumor suppressor in ovarian cancer. Targeting the circMETTL6/NONO/GDF15 axis presents a potential therapeutic avenue for ovarian cancer treatment.