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

Author

Listed:
  • Marco Napoli

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

  • Xiaobo Li

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

  • Hayley D. Ackerman

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

  • Avani A. Deshpande

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

  • Ivan Barannikov

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

  • Marlese A. Pisegna

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

  • Isabelle Bedrosian

    (The University of Texas M.D. Anderson Cancer Center)

  • Jürgen Mitsch

    (Advanced Data Analysis Centre
    School of Computer Sciences University of Nottingham)

  • Philip Quinlan

    (Advanced Data Analysis Centre
    School of Computer Sciences University of Nottingham)

  • Alastair Thompson

    (Baylor College of Medicine)

  • Kimal Rajapakshe

    (Baylor College of Medicine)

  • Cristian Coarfa

    (Baylor College of Medicine)

  • Preethi H. Gunaratne

    (University of Houston)

  • Douglas C. Marchion

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Anthony M. Magliocco

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Kenneth Y. Tsai

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

  • Elsa R. Flores

    (H. Lee Moffitt Cancer Center and Research Institute
    H. Lee Moffitt Cancer Center and Research Institute)

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.

Suggested Citation

  • Marco Napoli & Xiaobo Li & Hayley D. Ackerman & Avani A. Deshpande & Ivan Barannikov & Marlese A. Pisegna & Isabelle Bedrosian & Jürgen Mitsch & Philip Quinlan & Alastair Thompson & Kimal Rajapakshe &, 2020. "Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18973-w
    DOI: 10.1038/s41467-020-18973-w
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