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lncRNA DLEU2 regulates IKKα-mediated ¹³¹I resistance in thyroid carcinoma TPC-1 cells via the EZH2/H3K27me3 axis
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Abstract:
[Abstract] Objective: To investigate the mechanism by which lncRNA DLEU2 regulates IKKα-mediated radioiodine resistance in thyroid carcinoma (TC) through the EZH2/H3K27me3 axis. Methods: DLEU2 expression and its association with EZH2 in TC were analyzed using the TCGA database. Radioiodine-resistant TPC-1 cell (RR-TPC-1 cell) model and the nude mouse xenograft models were established. Following interventions including DLEU2 knockdown or overexpression (si-DLEU2/OE-DLEU2), EZH2 inhibition (UNC1999), and IKKα overexpression (OE-IKKα), gene and protein expression, histone modifications, cell proliferation, apoptosis, and tumorigenicity were detected by qPCR, Western blot, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), CCK-8 assay, flow cytometry, TUNEL staining, and xenograft tumor growth assay. Results: TCGA analysis revealed significant upregulation of DLEU2 in TC (P < 0.001), which was associated with poor prognosis (P = 0.0084) and was positively correlated with EZH2 expression (Pearson r = 0.390, P < 0.001). RIP assay revealed an interaction between EZH2 and DLEU2 (P < 0.05). In vitro experiments indicated that DLEU2 knockdown in RR-TPC-1 cells markedly reduced EZH2 and IKKα expression as well as H3K27me3 levels, inhibited NF-κB pathway activation (P < 0.05 or P < 0.01), suppressed cell proliferation and promoted cell apoptosis (all P < 0.05). DLEU2 knockdown combined with EZH2 inhibition further enhanced these effects while IKKα overexpression partially reversed these effects (P < 0.05 or P < 0.01). In vivo experiments further demonstrated that DLEU2 knockdown combined with EZH2 inhibition significantly inhibited xenograft growth and promoted tumor cell apoptosis (all P < 0.01), while IKKα overexpression partially reversed the above-mentioned anti-tumor effects (P < 0.05 or P < 0.01). Conclusion: lncRNA DLEU2, through recruiting EZH2 to catalyze H3K27me3 modification, indirectly activates the IKKα/NF-κB signaling and establishes a positive feedback loop, which mediates 131I resistance in TPC-1 cells.
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