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Edited by Norbert Perrimon, Harvard Medical School, Boston, MA, and approved September 10, 2020 (received for review June 30, 2020)
Significance
Dysregulation of the evolutionarily conserved Hippo pathway has been implicated in multiple diseases including cancer. Here we identified the RNA-binding protein (RBP) Rox8 as a regulator of Hippo signaling-mediated tumorigenesis. Rox8 not only directly binds to the 3′ UTR of yki mRNA, but also interacts with miR-8 to recruit miRNA-loaded RISC to degrade yki mRNA and therefore impedes Yki-induced tissue growth. We further revealed that TIAR, the human ortholog of Rox8, has retained a conserved regulatory function in yki/YAP mRNA stability. Our work uncovers a collaborative action of RBP and miRNA in regulating Hippo signaling.
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.
Footnotes
↵1X.G. and Y.S. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: lei.xue{at}tongji.edu.cn , maxianjue{at}westlake.edu.cn, zxpkxy{at}126.com, or yangx{at}queensu.ca.
Author contributions: X.G., Y.S., X.M., X.Z., X.Y., and L.X. designed research; X.G., Y.S., T.A., H.J.J.v.R., J.L., S.Y., and P.L. performed research; X.G., Y.S., Z.L., M.Z., L.L., Y.Z., X.M., X.Z., X.Y., and L.X. analyzed data; and X.G., Y.S., and L.X. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2013449117/-/DCSupplemental.
Data Availability.
All study data are included in the article and supporting information. Some study data are available upon request.
Published under the PNAS license.
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Rox8 promotes microRNA-dependent yki messenger RNA decay
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