Cancer Cell
Volume 30, Issue 5, 14 November 2016, Pages 723-736
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Article
ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5

https://doi.org/10.1016/j.ccell.2016.10.001Get rights and content
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Highlights

  • ERK phosphorylation followed by Pin1-mediated isomerization impairs XPO5 activity

  • Downregulation of miR-122 leads to taxol resistance through septin-9 and MARK4

  • XPO5 phosphorylation correlates with poor prognosis in HCC patients

  • Pin1 and MARK4 are potential targets for clinical intervention in liver cancer

Summary

MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications.

Key words

ERK
Exportin-5
Pin1
nuclear export
miRNA
global downregulation
liver cancer
miR-122
drug resistance
microtubule

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