Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Cell Rep. 2023 Dec 26;42(12):113479. doi: 10.1016/j.celrep.2023.113479. Epub 2023 Nov 24.
Alternative polyadenylation (APA) plays a major role in controlling transcriptome diversity and therapeutic resistance of cancers. However, long non-coding RNAs (lncRNAs) involved in pathological APA remain poorly defined. Here, we functionally characterize LINC00921, a MED13L/P300-induced oncogenic lncRNA, and show that it is required for global regulation of APA in non-small cell lung cancer (NSCLC). LINC00921 shows significant potential for reducing NSCLC radiosensitivity, and high LINC00921 levels are associated with a poor prognosis for patients with NSCLC treated with radiotherapy. LINC00921 controls NUDT21 stability by facilitating binding of NUDT21 with the E3 ligase TRIP12. LINC00921-induced destabilization of NUDT21 promotes 3' UTR shortening of MED23 mRNA via APA, which, in turn, leads to elevated MED23 protein levels in cancer cells and nuclear translocation of β-catenin and thereby activates expression of multiple β-catenin/T cell factor (TCF)/lymphoid enhancer-binding factor (LEF)-regulated core oncogenes (c-Myc, CCND1, and BMP4). These findings highlight the importance of functionally annotating lncRNAs controlling APA and suggest the clinical potential of therapeutics for advanced NSCLC.
可变聚腺苷酸化 (APA) 在控制转录组多样性和癌症的治疗耐药性方面起着重要作用。然而，参与病理 APA 的长非编码 RNA (lncRNA) 仍未得到很好的定义。在这里，我们对 LINC00921 进行了功能表征，LINC00921 是一种 MED13L/P300 诱导的致癌 lncRNA，我们表明它是非小细胞肺癌 (NSCLC) 中 APA 全局调控所必需的。LINC00921 显示出显著降低 NSCLC 放射敏感性的潜力，并且 LINC00921 水平高与接受放射治疗的 NSCLC 患者预后不良相关。LINC00921 通过促进 NUDT21 与 E3 连接酶 TRIP12 的结合，控制 NUDT21 的稳定性。LINC00921 诱导的 NUDT21 不稳定通过 APA 促进 MED23 mRNA 的 3'UTR 缩短，从而导致癌细胞中 MED23 蛋白水平升高，β-catenin 核转位，并激活多个β-catenin/T 细胞因子 (TCF)/淋巴增强结合因子 (LEF) 调控的核心癌基因 (c-Myc、CCND1 和 BMP4) 的表达。这些发现强调了对控制 APA 的功能性注释 lncRNA 的重要性，并表明了针对晚期 NSCLC 的治疗方法的临床潜力。
