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

Benjamin Ory,Leif W Ellisen

doi:10.18632/oncotarget.244

Benjamin Ory, Leif W Ellisen

Open Access

https://doi.org/10.18632/oncotarget.244

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Journal: Oncotarget	Publication Date: Mar 23, 2011
Citations: 72	License type: cc-by

Affiliation: Massachusetts General Hospital, Harvard University

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.

Highlights

The p53 gene is the prototypical human tumor suppressor and is mutated or lost in the majority of human cancers
We used chromatin immunoprecipitation (ChIP) to map a p63 binding site with the miR-193a locus, and we showed using reporter assays that the canonical p53 family binding sequence within this p63-bound region was required for p63 dependent suppression of this miR
The difference in chemosensitivity observed in control versus antagomirtreated cells was correlated with induction of TAp73 proapoptotic transcriptional target genes, and this difference was abolished when TAp73 knockdown was performed prior to cisplatin treatment [14]. These findings argue that induction of miR-193a through the p63 and p73-dependent effects of cisplatin limits p73dependent chemosensitivity through direct feedback inhibition

Summary

Introduction

The p53 gene is the prototypical human tumor suppressor and is mutated or lost in the majority of human cancers. We observed direct binding of p73, as well as TAp73-dependent regulation of miR193a following cisplatin chemotherapy treatment, which is known to induce ∆Np63α degradation and TAp73 activation [14]. These findings suggested a feed-forward loop whereby ∆Np63α expression would suppress miR-193a and thereby increase TAp73 levels, while TAp73 would be involved in negative feedback regulation via its own 3’UTR and miR-193a (Figure 1).

Results

Conclusion