Journal
CANCER CELL
Volume 30, Issue 5, Pages 723-736Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2016.10.001
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Funding
- US NIH [R35CA197706, R01CA193244]
- Taiwan Ministry of Science and Technology [NSC99-2320-B400-008-MY3, NSC 99-2628-B002-024-MY3, 101-2917-I-564-052, MOST 105-2632-B-715-001, MOST 104-2320-B-715-002]
- Pelotonia Graduate Student Fellowship
- National Key Research & Development Program of China [2016YFA0502204]
- National Natural Science Foundation of China [81572739]
- American Cancer Society [IRG-67-003-50]
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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 Pint, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases micro tubule 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.
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