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

Christina G Towers,Joaquin M Espinosa,J Chuck Harrell,Carol A Sartorius,Charles M Perou,Peter Kabos,Jihye Kim,Heide L Ford,Anna L Guarnieri,Aik-Choon Tan,Chu-An Wang,Michael U.J Oliphant,Austin E Gillen,David J Drasin,Doug S Micalizzi,Michelle A Guney

doi:10.1038/ncomms10077

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.

Highlights

TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated
We further show that Six[1] decreases the level of p53 protein via simultaneous downregulation of ribosomal protein L26 (RPL26) and upregulation of miRNA-27a-3p, uncovering a competitive mechanism of p53 control working through its untranslated regions (UTRs)
We observed a decrease in p53 protein and p21 protein and messenger RNA (mRNA) expression in response to ionizing radiation-induced DNA damage in the presence of Six[1] (Fig. 2b; Supplementary Fig. 4)

Summary

Introduction

TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated. Phosphorylation in response to DNA damage inhibits the p53/MDM2 interaction, thereby stabilizing p53 and enabling its activation of downstream target genes to regulate tumour suppresson[3]. Binding of the ribosomal protein L26 (RPL26) to the p53-untranslated regions (UTRs) has been shown to require a double-stranded region of RNA (dsRNA) formed by the 50- and 30-UTRs of the p53 messenger RNA (mRNA). This binding leads to increased p53 translation, resulting in higher protein levels and an increase in p53-mediated apoptosis[10,11]. The molecular pathways that mediate Six1-induced phenotypes include VEGF-C upregulation, as well as activation of extracellular signalregulated kinase (ERK) and transforming growth factor-b (TGFb) signalling, with TGFb being regulated in part by Six[1] mediated induction of the miR-106b-25 cluster[15,16,17,18,19]

Methods

Results

Conclusion