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Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ

Oncogene volume 36, pages 3515–3527 (2017)Cite this article

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Abstract

Wild-type p53 (wtp53) is described as a tumour suppressor gene; mutations in this gene occur in many human cancers and promote oncogenic capacity. Here, we establish that the oncogenic activity of mutant p53 (mtp53) is driven by the WASP-interacting protein (WIP). WIP knockdown from mtp53-expressing glioblastoma and breast cancer cells (BCC) greatly reduced proliferation and growth capacity of cancer stem cell (CSC)-like cells and decreased CSC-like markers (CD133, CD44 or YAP/TAZ). mtp53 overexpression in human astrocytes enhanced their proliferative capacity in suspension culture and increased expression of CSC markers and WIP. WIP knockdown compromised tumour glioblastoma and BCC growth capacity in vivo. We show that WIP is phosphorylated by AKT2 and is regulated by mtp53/p63 through enhancement of PI3K/AKT2-mediated integrin/receptor recycling pathways. WIP regulates this oncogenic pathway by controlling YAP/TAZ stability. We thus establish a new CSC signalling pathway downstream of mtp53 in which AKT2 regulates WIP and controls YAP/TAZ stability.

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Acknowledgements

We thank Catherine Mark for editorial assistance. The proteomic analysis was performed in the proteomics facility of Centro Nacional de Biotecnología that belongs to ProteoRed, PRB2-ISCIII; we particularly acknowledge the exceptional work of Rosana Navajas. This work was supported by grants from the MICINN, the Plan Nacional of the Dirección General de Ciencia y Tecnología (SAF2012-39148-C03-01 to FW, SAF2013-45937-R to IMA and SAF2015-70368-R to both and SAF2013-43271-R to AC), the European Union (EU-FP7-2009-CT222887 to FW) and the Instituto de Salud Carlos III Centro de Investigación Biomédica en Red (CIBERNED).

Author contributions

ME and RG performed the experiments. ME, RG, IMA and FW designed the experiments and analysed the data, wrote the manuscript and provided editorial suggestions and criticisms. AC provided AKT-related reagents, suggestions and criticism.

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  1. M Escoll and R Gargini: These authors contributed equally to this work.

Authors and Affiliations

  1. Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma Madrid, Madrid, Spain

    M Escoll & F Wandosell

  2. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, Madrid, Spain

    M Escoll, A Cuadrado, I M Anton & F Wandosell

  3. Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, Madrid, Spain

    R Gargini & I M Anton

  4. Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Instituto de Investigación Sanitaria La Paz (IdiPaz) and Universidad Autónoma Madrid, Madrid, Spain

    A Cuadrado

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Correspondence to I M Anton or F Wandosell.

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Escoll, M., Gargini, R., Cuadrado, A. et al. Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ. Oncogene 36, 3515–3527 (2017). https://doi.org/10.1038/onc.2016.518

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