TP53 is mutated in 50% of all cancers, and is often functionally compromised in cancers where it is not mutated. 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 the ribosomal protein L26 (RPL26), a positive regulator of p53 translation. Mutation analysis confirms that RPL26, whose expression inversely correlates with Six1 expression in numerous tumor types, inhibits miR-27a binding to the p53 3’UTR and prevents microRNA-mediated translational inhibition of p53. Thus, through simultaneous downregulation of RPL26 and upregulation of miR-27a, Six1 efficiently lowers p53 levels despite regulation of p53 at the level of the proteasome. Consequently, Six1 overexpression, which is observed in numerous tumor types, leads to dramatic resistance to nutlins, as well as other therapies targeting the p53-MDM2 interaction.
Less...
More...