CircABHD2 Inhibits Malignant Progression of Endometrial Cancer by Regulating NAD+/NAMPT Metabolism Axis.

Abstract

Circular RNAs (circRNAs) perform important functions in the regulation of diverse physiological and pathological processes. CircABHD2 exhibits down-regulation in both endometrial cancer (EC) cells and tissues, but the biological roles and mechanisms of action in EC are still unclear. This study aims to provide a theoretical basis for the role of circABHD2 in EC and potential targets for individualized precision therapy. Dysregulated circRNAs were identified using RNA sequencing (RNA-Seq) from EC tissues and validated using RT-qPCR. CCK-8, colony formation assay, wound healing assay, transwell assay, cell cycle, and apoptosis assay were used to evaluate the effects of circABHD2 on EC cells. Metabolomics assay and western blot analyses were used to investigate the potential mechanisms of circABHD2. From sequencing of RNA (RNA-Seq) analysis of EC tissues, we obtained 19 dysregulated circRNAs, including 8 upregulated ones and 11 downregulated ones. Using RT-qPCR on 32 EC tissues and 19 normal endometrial tissues, we confirmed that circABHD2 was downregulated in EC tissues. The expression levels of circABHD2 were closely relevant to the International Federation of Gynecology and Obstetrics (FIGO) stage and differentiation degree of EC. Functional experiments demonstrated that overexpression of circABHD2 decreased proliferation, migration, invasion, and promoted cell apoptosis. Un-targeted metabolomic assay revealed 31 differential metabolites in EC cells overexpressing circABHD2. KEGG analysis of differential metabolites indicated that NAD⁺ is the core metabolite regulated by circABHD2. NAMPT is one key enzyme involved in the synthetic pathway responsible for NAD⁺. Subsequent experiments confirmed that by inhibiting NAMPT protein expression in EC cells, cirABHD2 can inhibit NAD⁺ level, suggesting that circABHD2 may inhibit EC by regulating the metabolic axis of NAD⁺/NAMPT. CircABHD2, a downregulated circRNA in EC cells and tissues, inhibits the malignant progression of EC via the NAD⁺/NAMPT metabolic axis. This discovery presents a promising diagnostic biomarker and potential therapeutic target for EC.