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Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation

The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing...

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Autores principales: Napoli, Marco, Li, Xiaobo, Ackerman, Hayley D., Deshpande, Avani A., Barannikov, Ivan, Pisegna, Marlese A., Bedrosian, Isabelle, Mitsch, Jürgen, Quinlan, Philip, Thompson, Alastair, Rajapakshe, Kimal, Coarfa, Cristian, Gunaratne, Preethi H., Marchion, Douglas C., Magliocco, Anthony M., Tsai, Kenneth Y., Flores, Elsa R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561725/
https://www.ncbi.nlm.nih.gov/pubmed/33056990
http://dx.doi.org/10.1038/s41467-020-18973-w
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author Napoli, Marco
Li, Xiaobo
Ackerman, Hayley D.
Deshpande, Avani A.
Barannikov, Ivan
Pisegna, Marlese A.
Bedrosian, Isabelle
Mitsch, Jürgen
Quinlan, Philip
Thompson, Alastair
Rajapakshe, Kimal
Coarfa, Cristian
Gunaratne, Preethi H.
Marchion, Douglas C.
Magliocco, Anthony M.
Tsai, Kenneth Y.
Flores, Elsa R.
author_facet Napoli, Marco
Li, Xiaobo
Ackerman, Hayley D.
Deshpande, Avani A.
Barannikov, Ivan
Pisegna, Marlese A.
Bedrosian, Isabelle
Mitsch, Jürgen
Quinlan, Philip
Thompson, Alastair
Rajapakshe, Kimal
Coarfa, Cristian
Gunaratne, Preethi H.
Marchion, Douglas C.
Magliocco, Anthony M.
Tsai, Kenneth Y.
Flores, Elsa R.
author_sort Napoli, Marco
collection PubMed
description The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.
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spelling pubmed-75617252020-10-19 Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation Napoli, Marco Li, Xiaobo Ackerman, Hayley D. Deshpande, Avani A. Barannikov, Ivan Pisegna, Marlese A. Bedrosian, Isabelle Mitsch, Jürgen Quinlan, Philip Thompson, Alastair Rajapakshe, Kimal Coarfa, Cristian Gunaratne, Preethi H. Marchion, Douglas C. Magliocco, Anthony M. Tsai, Kenneth Y. Flores, Elsa R. Nat Commun Article The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway. Nature Publishing Group UK 2020-10-14 /pmc/articles/PMC7561725/ /pubmed/33056990 http://dx.doi.org/10.1038/s41467-020-18973-w 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
Napoli, Marco
Li, Xiaobo
Ackerman, Hayley D.
Deshpande, Avani A.
Barannikov, Ivan
Pisegna, Marlese A.
Bedrosian, Isabelle
Mitsch, Jürgen
Quinlan, Philip
Thompson, Alastair
Rajapakshe, Kimal
Coarfa, Cristian
Gunaratne, Preethi H.
Marchion, Douglas C.
Magliocco, Anthony M.
Tsai, Kenneth Y.
Flores, Elsa R.
Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation
title Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation
title_full Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation
title_fullStr Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation
title_full_unstemmed Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation
title_short Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation
title_sort pan-cancer analysis reveals tap63-regulated oncogenic lncrnas that promote cancer progression through akt activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561725/
https://www.ncbi.nlm.nih.gov/pubmed/33056990
http://dx.doi.org/10.1038/s41467-020-18973-w
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