NORAD orchestrates endometrial cancer progression by sequestering FUBP1 nuclear localization to promote cell apoptosis

Tong Han,Yiding Bian,Wenwen Jia,Mengfei Wang,Xudong Guo,Xiang Hu,Jiuhong Kang,Yaqi Chen,Qizhi He,Yukang Wu,Xiaoping Wan

doi:10.1038/s41419-020-2674-y

Tong Han, Yiding Bian + Show 9 more

Open Access

https://doi.org/10.1038/s41419-020-2674-y

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Abstract

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.

Highlights

Endometrial cancer (EC), originating from the endometrium, is the most common malignant gynecological cancer in women, and its incidence is steadily increasing around the world without improved 5-year survival[1,2]
We found that NORAD expression was gradually decreased with the progression of EC compared with that in normal endometrial tissues (Fig. 1b)
Our results showed that the expression level of NORAD was correlated with Federation of Gynecology and Obstetrics (FIGO) stages and patient age, rather than other clinical factors, such as estrogen receptor (ER) expression, etc

Summary

Introduction

Endometrial cancer (EC), originating from the endometrium, is the most common malignant gynecological cancer in women, and its incidence is steadily increasing around the world without improved 5-year survival[1,2]. Emerging evidences support the notion that long noncoding RNAs (lncRNAs), a minimum length of 200 nucleotides, are considered as drivers of multiple cancer phenotypes, including tumor cells sustaining proliferation, viability, motility, and angiogenesis[4,5,6]. In view of the biological function and specific expression in tumor tissues, lncRNAs are served as biomarkers for tumor diagnosis and therapeutic targets[7,8]. Recent studies found that a highly conserved and abundantly expressed lncRNA, NORAD, could maintain genomic stability by decoying. Han et al Cell Death and Disease (2020)11:473 recognized as one of the cancer hallmarks and involved in tumor initiation and progression[12]. Several studies have revealed that NORAD had effects on tumor cell proliferation, apoptosis, and migration via binding with miRNAs or proteins[13]. The function and mechanism of NORAD involved in regulating EC formation and progression remain unexplored

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