CircFMN2 Boosts Sorafenib Resistance in Hepatocellular Carcinoma Cells via Upregulating CNBP by Restraining Ubiquitination

PURPOSE: Noncoding RNAs exert critical biological effects in hepatocellular carcinoma (HCC). The role of circFMN2, a newly discovered functional RNA in prostate cancer and colorectal cancer, was investigated for the first time in sorafenib-resistance HCC cells. METHODS: The level of circFMN2 was assessed via quantitative real-time PCR (qRT-PCR). Cell proliferation was detected via CCK-8 and colony formation assay. Cell apoptosis was measured via the TUNEL assay and flow cytometry analysis. A Western blot assay was conducted to detect the CCHC-type zinc finger nucleic acid binding protein (CNBP) level and ubiquitination. RNA pull-down assay and RNA immunoprecipitation were carried out to explore the interaction between circFMN2 and CNBP. RESULTS: CircFMN2 was highly expressed in multidrug-resistant (MDR) cells. CircFMN2 overexpression exerted pro-proliferation effects in sorafenib-treated HCC cells, while depletion of circFMN2 displayed negative effect on sorafenib-treated MDR cells. Moreover, CNBP was verified as the binding protein of circFMN2. CNBP was upregulated in MDR cells, which was achieved by inhibition of ubiquitination by circFMN2. Besides, CNBP overexpression was found to boost sorafenib resistance in HCC cells. CONCLUSIONS: CircFMN2 is aberrantly expressed in sorafenib-resistant HCC cells and contributes to sorafenib resistance in HCC cells via upregulation of CNBP by restraining ubiquitination.