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Nat Commun. 2015 Dec 21;6:10077. doi: 10.1038/ncomms10077.

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

Author information

1
Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.
2
Department of Pharmacology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.
3
Linda Crnic Institute for Down Syndrome, University of Colorado, Denver, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
4
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, Colorado 80203, USA.
5
Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815-6789, USA.
6
Department of Genetics, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
7
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
8
Department of Medicine, Division of Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, Colorado 80045, USA.
9
Integrated Physiology Program, Division of Reproductive Sciences, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.
10
Department of Pathology, University of Colorado, Denver, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, Colorado 80045, USA.

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.

PMID:
26687066
PMCID:
PMC4703841
DOI:
10.1038/ncomms10077
[Indexed for MEDLINE]
Free PMC Article

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