Editors' ChoiceCancer

ERK blocks pre-miRNA export

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Sci. Signal.  29 Nov 2016:
Vol. 9, Issue 456, pp. ec280
DOI: 10.1126/scisignal.aal4588

The multistep process of microRNA (miRNA) biogenesis involves transcription of the gene encoding the primary miRNA (pri-miRNA), cleavage of the pri-miRNA to the premature (pre-) miRNA, and nuclear export and additional processing of the pre-miRNA into the mature miRNA. Data from cancer cell lines suggests that nuclear-to-cytoplasmic export of pre-miRNAs is impaired in tumors, and decreased global miRNA abundance is associated with the metastatic progression of hepatocellular carcinoma (HCC). Sun et al. found that posttranslational modification of the pre-miRNA transport receptor exportin-5 (XPO5) promotes the development and drug resistance of HCC tumors in mice. Analysis of liver tumors and adjacent normal liver tissue from HCC patients revealed that XPO5 was more abundantly serine-phosphorylated and more localized to the nucleus in tumor cells than it was in adjacent normal cells. Various assays in liver cancer cell lines and transfected HEK 293T cells indicated that extracellular signal–regulated kinase (ERK)–mediated phosphorylation inhibited the nuclear export activity of XPO5 and hence suppressed the generation of mature miRNAs, including that of miR-122, an abundant liver miRNA that has diverse functions in liver physiology and as such has diverse targets, including transcripts associated with microtubule dynamics. Structural analysis of XPO5 combined with analyses of transfected or pharmacologically manipulated cells suggested that ERK-mediated phosphorylation promoted a conformational change in XPO5 that was facilitated by the prolyl isomerase PIN1. In a cohort of HCC patients, the phosphorylation of XPO5 positively correlated with that of ERK and was associated with decreased miR-122 abundance in the tumor and poor prognosis in the patient. ERK activation, XPO5 phosphorylation, or loss of miR-122 in a liver cancer cell line promoted resistance to the chemotherapeutic taxol, which interferes with microtubule breakdown during cell division. Taxol resistance and tumor growth were decreased in xenografts in mice by inhibition of PIN1 or the miR-122 target kinase MARK4. The findings uncover potential targets for drug development for treating patients with liver cancer.

H.-L. Sun, R. Cui, J. Zhou, K.-Y. Teng, Y.-H. Hsiao, K. Nakanishi, M. Fassan, Z. Luo, G. Shi, E. Tili, H. Kutay, F. Lovat, C. Vicentini, H.-L. Huang, S.-W. Wang, T. Kim, N. Zanesi, Y.-J. Jeon, T. J. Lee, J.-H. Guh, M.-C. Hung, K. Ghoshal, C.-M. Teng, Y. Peng, C. M. Croce, ERK activation globally downregulates miRNAs through phosphorylating exportin-5. Cancer Cell 30, 723–736 (2016). [PubMed]

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