The Six1 oncoprotein represses translation of P53 via concomitant regulation of RPL26 and microRNA-27a

Abstract

TP53 is described as the “guardian of the genome” due to its critical role in mediating DNA damage-induced cell cycle arrest and apoptosis. While TP53 is mutated in 50% of all cancers, its function is also thought to be compromised in many cancers where it is not mutated. Our data demonstrate that the homeoprotein Six1, which is overexpressed in numerous tumor types, decreases the levels of wild type p53 through a mechanism that does not involve the well-known negative regulator of p53, MDM2, or any other ubiquitin ligase that influences p53 degradation. Similarly, other known oncogenic pathways downstream of Six1 that impinge on MDM2 regulation of p53 are also dispensible for Six1 mediated regulation of p53, including Akt, ERK, and TGFβ signaling. Instead, Six1 regulates p53 via a novel, dual mechanism, involving up-regulation of the oncomir, microRNA-27a, which we show targets p53, and downregulation of the ribosomal protein L26 (RPL26), which enhances p53 translation. Interestingly, RPL26 and miR-27a bind proximal to each other on the p53 3’UTR, and mutation analysis confirms that RPL26 occludes miR-27a from binding and prevents microRNA mediated translational inhibition. Thus, we demonstrate for the first time a competitive mechanism of p53 regulation through its 3’UTR, which is exploited by Six1 to efficiently decrease p53 levels. Importantly, Six1 expression significantly correlates with decreased RPL26 across numerous tumor types, underscoring the relevance of this interaction to the human disease. Furthermore, our findings have implications for therapies targeting the MDM2-p53 interaction, and indeed we find that Six1 expression leads to marked resistance to nutlin therapies. Together, these data suggest that a well-known metastasis regulator, Six1, may act to promote tumor progression via decreasing the levels of p53.