Rox8 promotes microRNA-dependent yki messenger RNA decay
- 17 November 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (48), 30520-30530
- https://doi.org/10.1073/pnas.2013449117
Abstract
The Hippo pathway is an evolutionarily conserved regulator of organ growth and tumorigenesis. In Drosophila, oncogenic RasV12 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 Drosophila RasV12/lgl−/− in vivo tumor model and identified Rox8, a RNA-binding protein (RBP), as a positive regulator of the Hippo pathway. We found that Rox8 overexpression suppresses whereas Rox8 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 yki 3′ UTR, recruits and stabilizes the targeting of miR-8–loaded RISC, which accelerates the decay of yki messenger RNA (mRNA). Moreover, TIAR, the human ortholog of Rox8, is able to promote the degradation of yki mRNA when introduced into Drosophila and destabilizes YAP 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.Funding Information
- National Natural Science Foundation of China (31771595, 31970536)
- Shanghai Committee of Science and Technoledge (09DZ2260100, 18430711600 and 18140900400)
- China Postdoctoral Science Foundation (2000229071)
- National Natural Science Foundation of China (81671716)
- Canadian Institute of Health Research (CIHR, MOP119325, MOP148629)
- Canadian Cancer Society (CCS)
- Team for Growth Control and Size Innovative Research (201804016)
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