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TMPRSS2–ERG gene fusions induce prostate tumorigenesis by modulating microRNA miR-200c

Oncogene volume 33, pages 5183–5192 (2014)Cite this article

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Abstract

Chromosomal translocations that juxtapose the androgen-sensitive transmembrane protease, serine 2 (TMPRSS2) gene promoter to the oncogenic ETS-family transcription factor ERG result in excessive ERG overexpression in approximately 50% of prostate cancer (PCa) patients. Although numerous studies have investigated ERG-downstream genes, such studies have not attempted to examine miRNAs, which however are emerging to be important regulators of cancer. Through bioinformatics analysis of ChIP-Seq ERG data and miRNA expression profiling data we nominated miR-200c as a direct target of ERG. Experimentation of PCa cells with ERG overexpression or knockdown demonstrated that ERG directly repressed miR-200c expression by physically binding to the erythroblast transformation-specific (ETS) motif within its promoter. Consequently, miR-200c was downregulated in ERG-positive PCa, and miR-200c target gene expression was restored. In addition, the expression pattern of miR-200c target genes predicted ERG status in clinical PCa specimens. Furthermore, miR-200c was found to be important in modulating ZEB1 upregulation by ERG. Most importantly, miR-200c reconstitution fully reversed ERG-induced epithelial-to-mesenchymal transition (EMT), cell migration and invasion. Therefore, our study report miR-200c as the first miRNA target of ERG and a critical inhibitor of PCa cell motility. Therapeutic delivery of miR-200c may provide personalized treatment for patients with the molecular subtype of PCa that harbors TMPRSS2–ERG gene fusions.

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Acknowledgements

We thank Jianjun Yu for helpful discussions. This work was supported by funding from the NIH R01CA172384 (to JY), NIH R00CA129565 (to JY) the Research Scholar Award RSG-12-085-01 (to JY) from the American Cancer Society and the NRSA pre-doctoral fellowship T32 CA080621 (to JK).

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  1. Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    J Kim, L Wu, J C Zhao, H-J Jin & J Yu

  2. Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    J Yu

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Kim, J., Wu, L., Zhao, J. et al. TMPRSS2–ERG gene fusions induce prostate tumorigenesis by modulating microRNA miR-200c. Oncogene 33, 5183–5192 (2014). https://doi.org/10.1038/onc.2013.461

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