A microRNA-dependent circuit controlling p63/p73 homeostasis: p53 family cross-talk meets therapeutic opportunity

Abstract

The p53 family transcription factors p53, p63 and p73 make diverse contributions in development and cancer. Mutation or deletion of p53 is observed in the majority of human cancers. In contrast, p63 and p73 are not lost in cancer but mediate distinct genetic roles in normal and tumor-specific contexts: p73 promotes genome stability and mediates chemosensitivity, while p63 largely lacks these p53-like functions and instead promotes proliferation and cell survival. We recently uncovered a mechanism which maintains p63/p73 homeostasis within the epithelium through direct transcriptional regulation of microRNAs (miRs). We discovered that several of the top p63-regulated miRs target p73 for inhibition, including miR-193a-5p, a direct p63/p73 transcriptional target which is repressed by p63 and activated by p73 both in vitro and in vivo. The resulting feed-forward circuit involving p63, miR-193a-5p and p73 controls p73 levels, cell viability and DNA damage susceptibility in certain cancers including squamous cell carcinoma. Here, we discuss the evolutionary implications of this regulatory circuit, which may point to a general mechanism of miR-mediated cross-talk within transcription factor gene families. Additionally, we suggest that inducible chemoresistance mediated by this miR-dependent mechanism might be an attractive target for therapeutic intervention.

Figure 1. A miR-mediated negative feed-forward loop maintains p63/p73 homeostasis in the epithelium

A. Proposed miR-mediated feed-forward circuit. P63 is a transcriptional repressor of miRs that target p73 for inhibition. One of these miRs, miR-193a, is a direct transcriptional target repressed by p63 and activated by p73. P63 also inhibits p73 function by direct physical interaction and by binding to shared promoter elements. This p63/p73 circuit is unique in involving two transcription factors which are members of a conserved gene family. Additionally, it is remarkable for implicating three levels of direct regulation: transcriptional regulation by p63 and p73 of the miR; post-transcriptional regulation by the miR of p73, and post-translational regulation by p63 of p73 activity. B. Schematic expression levels of p63, p73 and miR-193a in basal cells of stratified squamous epithelium (normal) and squamous cell carcinoma (tumor). Both p63 and p73 are up-regulated in tumors relative to normal cells. Increased p63 expression in tumors mediates miR-193a repression, which in turn contributes to increased p73 mRNA and thereby maintains a balanced p63/p73 ratio. Disruption of the network by miR inhibition increases p73 activity, leading to impaired cellular viability and enhanced chemosensitivity.