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

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, Carol A. Sartorius, Aik-Choon Tan, Charles M. Perou, Joaquin M. Espinosa and Heide L. Ford ()
Additional contact information
Christina G. Towers: Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus
Anna L. Guarnieri: University of Colorado, Denver, Anschutz Medical Campus
Doug S. Micalizzi: Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus
J. Chuck Harrell: University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center
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
Michael U.J. Oliphant: University of Colorado, Denver, Anschutz Medical Campus
David J. Drasin: University of Colorado, Denver, Anschutz Medical Campus
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
Joaquin M. Espinosa: University of Colorado, Denver, Anschutz Medical Campus
Heide L. Ford: Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms10077

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