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Ubc9 promotes breast cell invasion and metastasis in a sumoylation-independent manner

Oncogene volume 29, pages 1763–1772 (2010)Cite this article

Abstract

Ubc9 is an E2-conjugating enzyme that transfers the activated small ubiquitin-like modifier (SUMO) to protein substrates, and thus it has an important function in sumoylation-mediated cellular pathways. We have earlier reported that Ubc9 promotes tumor growth in the xenograft mouse model using breast cancer cell line MCF-7 in part through regulation of Bcl-2 expression. In this study, we show that ectopic expression of wild-type Ubc9 (Ubc9-WT) promotes cell invasion and metastasis. Surprisingly, the dominant negative mutant Ubc9 (Ubc9-DN) also causes the same phenotype, indicating that the ability of Ubc9 to promote invasion and metastasis is distinct from its ability to conjugate SUMO to protein substrates. Of considerable interest, several microRNAs such as miR-224 are regulated by Ubc9. Although ectopic expression of Ubc9 causes downregulation of miR-224, suppression of Ubc9 by Ubc9-siRNAs leads to its upregulation. We further show that miR-224 can inhibit cell invasion and directly targets CDC42 and CXCR4, and that suppression of CDC42 and CXCR4 by RNAi causes inhibition of Ubc9-mediated invasion. Together, these results show a molecular link between Ubc9 and the metastasis genes such as CDC42 and CXCR4, and thus provide new insight into the mechanism by which Ubc9 promotes tumor invasion and metastasis.

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Abbreviations

miRNA:

microRNA

PCR:

polymerase chain reaction

RT:

reverse transcription

SUMO:

small ubiquitin-like modifier

UTR:

untranslated region

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Acknowledgements

We are grateful to Dr Joan Massagué for providing LM2-4142 cells. This study is supported by grants CA102630 from NCI and postdoctoral fellowship award from Illinois Department of Public Health.

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Authors and Affiliations

  1. Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA

    S Zhu, M Sachdeva, F Wu, Z Lu & Y -Y Mo

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  1. S Zhu
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  2. M Sachdeva
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  3. F Wu
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  4. Z Lu
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Correspondence to Y -Y Mo.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Zhu, S., Sachdeva, M., Wu, F. et al. Ubc9 promotes breast cell invasion and metastasis in a sumoylation-independent manner. Oncogene 29, 1763–1772 (2010). https://doi.org/10.1038/onc.2009.459

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