Long noncoding RNAs (lncRNAs) are emerging as critical regulators in tumor initiation and progression. However, the biological mechanisms and potential clinical application of lncRNA NORAD in endometrial cancer (EC) remain unknown. Herein, we identified NORAD underwent promoter hypermethylation-associated downregulation in EC. Epigenetic inactivation of NORAD was correlated with EC progression (FIGO stage) and poor outcome. Overexpression of NORAD significantly inhibited cell growth and promoted apoptosis in EC cells. Mechanistic studies revealed that multiple regions of NORAD served as a platform for binding with the central domain of anti-apoptotic factor FUBP1. Our findings further indicated that the NORAD/FUBP1 interaction attenuated FUBP1 nuclear localization and thus impaired the occupancies of FUBP1 on its target pro-apoptotic gene promoters, resulting in apoptosis induction in EC. Moreover, knockdown of NORAD promoted tumor growth in the xenograft mice model. While, introduction of NORAD-4 fragment, which bound with FUBP1, successfully reversed tumor growth and apoptosis inhibition mediated by NORAD knockdown in vivo. Our findings provide mechanistic insight into the critical roles of NORAD as a tumor suppressor in EC progression. NORAD could possibly serve as a novel prognostic biomarker and provide the rationale for EC therapy.

长的非编码RNA（lncRNA）逐渐成为肿瘤发生和发展中的关键调节因子。然而，lncRNA NORAD在子宫内膜癌（EC）中的生物学机制和潜在的临床应用仍然未知。在本文中，我们确定了NORAD在EC中经历了启动子超甲基化相关的下调。NORAD的表观遗传失活与EC进展（FIGO阶段）和不良预后相关。NORAD的过表达显着抑制细胞生长并促进EC细胞凋亡。机理研究表明，NORAD的多个区域可作为与抗凋亡因子FUBP1中心域结合的平台。我们的发现进一步表明，NORAD / FUBP1相互作用减弱了FUBP1的核定位，从而削弱了FUBP1在其靶促凋亡基因启动子上的占有率，从而导致EC中的凋亡诱导。而且，在异种移植小鼠模型中，NORAD的敲低促进了肿瘤的生长。同时，引入与FUBP1结合的NORAD-4片段成功逆转了由NORAD体内敲除介导的肿瘤生长和细胞凋亡抑制。我们的发现为NORAD作为EC进程中的肿瘤抑制因子的关键作用提供了机械方面的见解。NORAD可以作为一种新的预后生物标志物，并为EC治疗提供依据。与FUBP1结合的蛋白成功地逆转了NORAD体内介导的肿瘤生长和凋亡抑制。我们的发现为NORAD在EC进展中作为肿瘤抑制因子的关键作用提供了机械学见解。NORAD可以作为一种新的预后生物标志物，并为EC治疗提供依据。与FUBP1结合的蛋白成功地逆转了NORAD体内介导的肿瘤生长和凋亡抑制。我们的发现为NORAD作为EC进程中的肿瘤抑制因子的关键作用提供了机械方面的见解。NORAD可以作为一种新的预后生物标志物，并为EC治疗提供依据。