Rox8 promotes microRNA-dependentykimessenger RNA decay
The Hippo pathway is an evolutionarily conserved regulator of organ growth and tumorigenesis. InDrosophila, oncogenic RasV12cooperates 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 theDrosophila RasV12/lgl−/−in vivo tumor model and identified Rox8, a RNA-binding protein (RBP), as a positive regulator of the Hippo pathway. We found thatRox8overexpression suppresses whereasRox8depletion 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 theyki3′ UTR, recruits and stabilizes the targeting of miR-8–loaded RISC, which accelerates the decay ofykimessenger RNA (mRNA). Moreover, TIAR, the human ortholog of Rox8, is able to promote the degradation ofykimRNA when introduced intoDrosophilaand destabilizesYAPmRNA 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.