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

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-asso...

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Autores principales: Han, Tong, Wu, Yukang, Hu, Xiang, Chen, Yaqi, Jia, Wenwen, He, Qizhi, Bian, Yiding, Wang, Mengfei, Guo, Xudong, Kang, Jiuhong, Wan, Xiaoping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303217/
https://www.ncbi.nlm.nih.gov/pubmed/32555178
http://dx.doi.org/10.1038/s41419-020-2674-y
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author Han, Tong
Wu, Yukang
Hu, Xiang
Chen, Yaqi
Jia, Wenwen
He, Qizhi
Bian, Yiding
Wang, Mengfei
Guo, Xudong
Kang, Jiuhong
Wan, Xiaoping
author_facet Han, Tong
Wu, Yukang
Hu, Xiang
Chen, Yaqi
Jia, Wenwen
He, Qizhi
Bian, Yiding
Wang, Mengfei
Guo, Xudong
Kang, Jiuhong
Wan, Xiaoping
author_sort Han, Tong
collection PubMed
description 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.
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spelling pubmed-73032172020-06-22 NORAD orchestrates endometrial cancer progression by sequestering FUBP1 nuclear localization to promote cell apoptosis Han, Tong Wu, Yukang Hu, Xiang Chen, Yaqi Jia, Wenwen He, Qizhi Bian, Yiding Wang, Mengfei Guo, Xudong Kang, Jiuhong Wan, Xiaoping Cell Death Dis Article 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. Nature Publishing Group UK 2020-06-18 /pmc/articles/PMC7303217/ /pubmed/32555178 http://dx.doi.org/10.1038/s41419-020-2674-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Han, Tong
Wu, Yukang
Hu, Xiang
Chen, Yaqi
Jia, Wenwen
He, Qizhi
Bian, Yiding
Wang, Mengfei
Guo, Xudong
Kang, Jiuhong
Wan, Xiaoping
NORAD orchestrates endometrial cancer progression by sequestering FUBP1 nuclear localization to promote cell apoptosis
title NORAD orchestrates endometrial cancer progression by sequestering FUBP1 nuclear localization to promote cell apoptosis
title_full NORAD orchestrates endometrial cancer progression by sequestering FUBP1 nuclear localization to promote cell apoptosis
title_fullStr NORAD orchestrates endometrial cancer progression by sequestering FUBP1 nuclear localization to promote cell apoptosis
title_full_unstemmed NORAD orchestrates endometrial cancer progression by sequestering FUBP1 nuclear localization to promote cell apoptosis
title_short NORAD orchestrates endometrial cancer progression by sequestering FUBP1 nuclear localization to promote cell apoptosis
title_sort norad orchestrates endometrial cancer progression by sequestering fubp1 nuclear localization to promote cell apoptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303217/
https://www.ncbi.nlm.nih.gov/pubmed/32555178
http://dx.doi.org/10.1038/s41419-020-2674-y
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