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The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p

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  • Christina G. Towers

    (Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus
    University of Colorado, Denver, Anschutz Medical Campus)

  • Anna L. Guarnieri

    (University of Colorado, Denver, Anschutz Medical Campus
    Linda Crnic Institute for Down Syndrome, University of Colorado, Denver, Anschutz Medical Campus
    Cellular and Developmental Biology, University of Colorado, Boulder
    Howard Hughes Medical Institute)

  • Doug S. Micalizzi

    (Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus
    Present address: Dana-Farber/Partners Cancer Care Hematology/Oncology Fellowship Program, Division of Hematology/Oncology, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA)

  • J. Chuck Harrell

    (University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center
    University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center
    Present address: Department of Pathology, Massey Cancer Center, Virginia Commonwealth University, 1101 East Marshall St., Richmond, Virginia 23298, USA)

  • Austin E. Gillen

    (University of Colorado, Denver, Anschutz Medical Campus)

  • Jihye Kim

    (University of Colorado, Denver, Anschutz Medical Campus)

  • Chu-An Wang

    (University of Colorado, Denver, Anschutz Medical Campus
    Present address: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 70101, Taiwan)

  • Michael U.J. Oliphant

    (University of Colorado, Denver, Anschutz Medical Campus
    Integrated Physiology Program, University of Colorado, Denver, Anschutz Medical Campus)

  • David J. Drasin

    (University of Colorado, Denver, Anschutz Medical Campus
    Present address: BluePrint Research Group, 235 Montgomery St. Suite 804, San Francisco, California 94104, USA)

  • Michelle A. Guney

    (University of Colorado, Denver, Anschutz Medical Campus)

  • Peter Kabos

    (University of Colorado, Denver, Anschutz Medical Campus)

  • Carol A. Sartorius

    (University of Colorado, Denver, Anschutz Medical Campus)

  • Aik-Choon Tan

    (University of Colorado, Denver, Anschutz Medical Campus)

  • Charles M. Perou

    (University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center
    University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center)

  • Joaquin M. Espinosa

    (University of Colorado, Denver, Anschutz Medical Campus
    Linda Crnic Institute for Down Syndrome, University of Colorado, Denver, Anschutz Medical Campus
    Cellular and Developmental Biology, University of Colorado, Boulder
    Howard Hughes Medical Institute)

  • Heide L. Ford

    (Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus
    University of Colorado, Denver, Anschutz Medical Campus
    Integrated Physiology Program, University of Colorado, Denver, Anschutz Medical Campus)

Abstract

TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated. Here we demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26). Mutation analysis confirms that RPL26 inhibits miR-27a binding and prevents microRNA-mediated downregulation of p53. The clinical relevance of this interaction is underscored by the finding that Six1 expression strongly correlates with decreased RPL26 across numerous tumour types. Importantly, we find that Six1 expression leads to marked resistance to therapies targeting the p53–MDM2 interaction. Thus, we identify a competitive mechanism of p53 regulation, which may have consequences for drugs aimed at reinstating p53 function in tumours.

Suggested Citation

  • Christina G. Towers & Anna L. Guarnieri & Doug S. Micalizzi & J. Chuck Harrell & Austin E. Gillen & Jihye Kim & Chu-An Wang & Michael U.J. Oliphant & David J. Drasin & Michelle A. Guney & Peter Kabos , 2015. "The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10077
    DOI: 10.1038/ncomms10077
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