lncRNA DLEU2通过EZH2/H3K27me3轴调控IKKα介导甲状腺癌TPC-1细胞131I抵抗OA

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=0.008 4)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 IKK α 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.