title: The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p.
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.
authors.affiliation: Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.|Department of Pharmacology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Christina G
authors.initials: CG
authors.lastname: Towers
authors.affiliation: Department of Pharmacology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.|Linda Crnic Institute for Down Syndrome, University of Colorado, Denver, Anschutz Medical Campus, Aurora, Colorado 80045, USA.|Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, Colorado 80203, USA.|Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815-6789, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Guarnieri
authors.affiliation: Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Doug S
authors.initials: DS
authors.lastname: Micalizzi
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.|Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
authors.forename: J Chuck
authors.initials: JC
authors.lastname: Harrell
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Austin E
authors.identifier: http://orcid.org/0000-0003-2928-6308
authors.initials: AE
authors.lastname: Gillen
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Chu-An
authors.initials: CA
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.|Integrated Physiology Program, Division of Reproductive Sciences, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Michael U J
authors.initials: MUJ
authors.lastname: Oliphant
authors.affiliation: Department of Pharmacology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Drasin
authors.affiliation: Department of Pharmacology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Guney
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Kabos
authors.affiliation: Department of Pathology, University of Colorado, Denver, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Sartorius
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.|Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Department of Pharmacology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.|Linda Crnic Institute for Down Syndrome, University of Colorado, Denver, Anschutz Medical Campus, Aurora, Colorado 80045, USA.|Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, Colorado 80203, USA.|Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815-6789, USA.
authors.forename: Joaquin M
authors.initials: JM
authors.lastname: Espinosa
authors.affiliation: Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.|Department of Pharmacology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.|Integrated Physiology Program, Division of Reproductive Sciences, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Heide L
authors.initials: HL
authors.lastname: Ford
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; C489216:RPL26 protein, human; D012269:Ribosomal Proteins; C099236:SIX1 protein, human; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2