Rox8 promotes microRNA-dependent <i>yki</i> messenger RNA decay.

Abstract

The Hippo pathway is an evolutionarily conserved regulator of organ growth and tumorigenesis. In <i>Drosophila</i>, oncogenic Ras^V12 cooperates with loss-of-cell polarity to promote Hippo pathway-dependent tumor growth. To identify additional factors that modulate this signaling, we performed a genetic screen utilizing the <i>Drosophila Ras</i>^<i>V12</i><i>/lgl</i>^<i>-/-</i> in vivo tumor model and identified Rox8, a RNA-binding protein (RBP), as a positive regulator of the Hippo pathway. We found that <i>Rox8</i> overexpression suppresses whereas <i>Rox8</i> depletion potentiates Hippo-dependent tissue overgrowth, accompanied by altered Yki protein level and target gene expression. Mechanistically, Rox8 directly binds to a target site located in the <i>yki</i> 3' UTR, recruits and stabilizes the targeting of miR-8-loaded RISC, which accelerates the decay of <i>yki</i> messenger RNA (mRNA). Moreover, TIAR, the human ortholog of Rox8, is able to promote the degradation of <i>yki</i> mRNA when introduced into <i>Drosophila</i> and destabilizes <i>YAP</i> mRNA in human cells. Thus, our study provides in vivo evidence that the Hippo pathway is posttranscriptionally regulated by the collaborative action of RBP and microRNA (miRNA), which may provide an approach for modulating Hippo pathway-mediated tumorigenesis.