CircMBOAT2 promotes FASN-mediated lipid metabolism reprogramming and progression in intrahepatic cholangiocarcinoma

Background: The carcinogenic role of FASN by regulating lipid metabolism reprogramming has been well established in multiple tumors. However, whether mechanisms during intrahepatic cholangiocarcinoma (ICC) progression such as circRNAs regulate FASN expression remains unknown. Methods: Five paired ICC and adjacent normal tissues were used to screen the lipid metabolism-associated differentially expressed circRNAs by high-throughput RNA sequencing; the biological role of circMBOAT2 was determined by gain or loss of function experiments. Fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were used to analyze the interaction of circMBOAT2 with PTBP1 and PTBP1 with FASN. Coimmunoprecipitation (co-IP) was used to investigate the ubiquitin binding of PTBP1. Non-targeted lipidomics was applied to detect changes in metabolite composition. Results: CircMBOAT2 (has_circ_0007334 in circBase) was frequently upregulated in ICC tissues and correlated with tumor size. Knockdown circMBOAT2 inhibits proliferation of ICC cells. Mechanistically, circMBOAT2 combines with PTBP1 and protect PTBP1 from ubiquitin/proteasome-dependent degradation, impairing the function of PTBP1 to transfer FASN mRNA from the nucleus to the cytoplasm. Moreover, circMBOAT2 and FASN have the same effect on fatty acid profile, unsaturated fatty acids instead of saturated fatty acids are primarily regulated and associated with malignant behaviors of ICC cells. Conclusions: Our results identified that circMBOAT2 stabilized PTBP1 and facilitated ICC lipid metabolic reprogramming via the modulation of FASN mRNA cytoplasmic export, suggesting that circMBOAT2 may serve as an available therapeutic target for ICC with active lipid metabolism.