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Mutant p53 inhibits miRNA biogenesis by interfering with the microprocessor complex

Oncogene volume 35, pages 3760–3770 (2016)Cite this article

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Abstract

Downregulation of microRNAs (miRNAs) is commonly observed in cancers and promotes tumorigenesis suggesting that miRNAs may function as tumor suppressors. However, the mechanism through which miRNAs are regulated in cancer, and the connection between oncogenes and miRNA biogenesis remain poorly understood. The TP53 tumor-suppressor gene is mutated in half of human cancers resulting in an oncogene with gain-of-function activities. Here we demonstrate that mutant p53 (mutp53) oncoproteins modulate the biogenesis of a subset of miRNAs in cancer cells inhibiting their post-transcriptional maturation. Interestingly, among these miRNAs several are also downregulated in human tumors. By confocal, co-immunoprecipitation and RNA-chromatin immunoprecipitation experiments, we show that endogenous mutp53 binds and sequesters RNA helicases p72/82 from the microprocessor complex, interfering with Drosha-pri-miRNAs association. In agreement with this, the overexpression of p72 leads to an increase of mature miRNAs levels. Moreover, functional experiments demonstrate the oncosuppressive role of mutp53-dependent miRNAs (miR-517a, −519a, −218, −105). Our study highlights a previously undescribed mechanism by which mutp53 interferes with Drosha-p72/82 association leading, at least in part, to miRNA deregulation observed in cancer.

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Acknowledgements

We thank Dr Vittorio Sartorelli for the p72 expression vector, Dr Silvia Bacchetti and Silvia Soddu for interesting discussions on the manuscript, Maria Pia Gentileschi for technical advice, Daniela Bona for secretary assistance. Aymone Gurtner and Gianluca Bossi were supported by a Fondazione Umberto Veronesi Fellowship; Dawid Walerych was a recipient of the FEBS postdoctoral fellowship. This work has been supported by grant from AIRC to AG (MFAG 11752); from AIRC to GP (IG 13234); from AIRC (Special Program Molecular Clinical Oncology ‘5 per mille’) (grant no. 10016) to GDS and from Italian Ministry of Health to GDS.

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Authors and Affiliations

  1. Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy

    F Garibaldi, E Falcone, D Trisciuoglio, G Bossi, G Piaggio & A Gurtner

  2. Institute for System Analysis and Computer Science “Antonio Ruberti”, National Research Council, Rome, Italy

    T Colombo & P Paci

  3. SysBio Centre for Systems Biology, Rome, Italy

    T Colombo & P Paci

  4. Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste, Italy

    K Lisek, D Walerych & G Del Sal

  5. Dipartimento di Scienze della Vita-Università degli Studi di Trieste, Trieste, Italy

    K Lisek & G Del Sal

  6. Department of Research, Advanced Diagnostics, and Technological Innovation, Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy

    G Bossi

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  1. F Garibaldi
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Garibaldi, F., Falcone, E., Trisciuoglio, D. et al. Mutant p53 inhibits miRNA biogenesis by interfering with the microprocessor complex. Oncogene 35, 3760–3770 (2016). https://doi.org/10.1038/onc.2016.51

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