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.

Abstract

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.

Citation

Napoli, M., Li, X., Ackerman, H. D., Deshpande, A. A., Barannikov, I., Pisegna, M. A., Bedrosian, I., Mitsch, J., Quinlan, P., Thompson, A., Rajapakshe, K., Coarfa, C., Gunaratne, P. H., Marchion, D. C., Magliocco, A. M., Tsai, K. Y., & Flores, E. R. (2020). Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation. Nature Communications, 11, Article 5156. https://doi.org/10.1038/s41467-020-18973-w

• Journal Article Type: Article
• Acceptance Date: Sep 24, 2020
• Online Publication Date: Oct 14, 2020
• Publication Date: 2020-12
• Deposit Date: Jun 17, 2024
• Publicly Available Date: Jun 20, 2024
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Article Number: 5156
• DOI: https://doi.org/10.1038/s41467-020-18973-w
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Physics and Astronomy; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/4974453
• Publisher URL: https://www.nature.com/articles/s41467-020-18973-w