MicroRNA (miRNA) dysregulation is associated with the tumorigenesis and development of numerous human cancers. The defect in miRNA biogenesis is the main cause of miRNA dysregulation. We previously demonstrated that ERK-induced phosphorylation of XPO5 followed by peptidyl-prolyl cis/trans isomerase Pin1-mediated isomerization downregulates miRNA expression and contributes to hepatocellular carcinoma (HCC) development. However, how Pin1 precisely regulates miRNA biogenesis in HCC remains elusive. Here we reveal that Pin1 has a pivotal role in the miRNA maturation process by modulating phosphorylated Serine-Proline (pS-P) motif of XPO5 in a phosphorylation-dependent manner. By recognizing and binding to XPO5 via its WW domain, Pin1 catalyzes the conformation change of XPO5 and diminishes XPO5 ability to export pre-miRNAs from the nucleus to the cytoplasm, resulting in the reduced mature miRNA levels and promoted HCC development. Furthermore, downregulation of Pin1 by shRNA restores XPO5-dependent pre-miRNA export and effective biogenesis of mature miRNAs, leading to both in vitro and in vivo HCC inhibition. Therefore, our research discloses a new posttranscriptional regulatory mechanism of miRNA biosynthesis and provides the experimental basis for a novel HCC therapy by targeting Pin1.
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This work was supported by National Key R&D Program of China (2017YFA0504304 and 2016YFA0502204 to Y.P.), National Natural Science Foundation of China (81772960 and 81572739 to Y.P.), China Postdoctoral Science Foundation (2017M612976 to W.P.). We thank Dr Yih-Cherng Liou (Department of Biological Science, National University of Singapore) for providing the plasmids His-Pin1, His-Pin1 WW, and His-Pin1 PPIase.
J.L.,W.P., X.F., X.L., and Z.X. performed cell culture, biochemistry, cell biology, and xenograft experiments. Y.Z. prepared the recombinant proteins. H.L.S and J.K.Z. prepared the lentivirus and stable cell lines. H.L.S., J.K.Z., and J.H. constructed the plasmids. J.L., W.P., and Y.P. wrote the manuscript. L.L. provided patients’ samples. Y.P. and Y.Q.W. oversaw the experimental design and data analysis.
Conflict of interests
The authors declare that they have no conflict of interest.
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