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Regulation of several androgen-induced genes through the repression of the miR-99a/let-7c/miR-125b-2 miRNA cluster in prostate cancer cells

Oncogene volume 33, pages 1448–1457 (2014)Cite this article

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Abstract

The androgen receptor (AR) stimulates and represses gene expression to promote the initiation and progression of prostate cancer. Here, we report that androgen represses the miR-99a/let7c/125b-2 cluster through AR and anti-androgen drugs block the androgen-repression of the miRNA cluster. AR directly binds to the host gene of the miR-99a/let7c/125b-2 cluster, LINC00478. Expression of the cluster is repressed or activated by chromatin remodelers EZH2 or JMJD3 in the presence or absence of androgen, respectively. Bioinformatics analysis reveals a significant enrichment of targets of miR-99a, let-7c and miR-125b in androgen-induced gene sets, suggesting that downregulation of the miR-99a/let7c/125b-2 cluster by androgen protects many of their target mRNAs from degradation and indirectly assists in the gene induction. We validated the hypothesis with 12 potential targets of the miR-99a/let7c/125b-2 cluster induced by androgen: 9 out of the 12 mRNAs are downregulated by the microRNA cluster. To ascertain the biological significance of this hypothesis, we focused on IGF1R, a known prostate cancer growth factor that is induced by androgen and directly targeted by the miR-99a/let7c/125b-2 cluster. The androgen-induced cell proliferation is ameliorated to a similar extent as anti-androgen drugs by preventing the repression of the microRNAs or induction of IGF1R in androgen-dependent prostate cancer cells. Expression of a microRNA-resistant form of IGF1R protects these cells from inhibition by the miR-99a/let7c/125b-2 cluster. These results indicate that a thorough understanding of how androgen stimulates prostate cancer growth requires not only an understanding of genes directly induced/repressed by AR, but also of genes indirectly induced by AR through the repression of key microRNAs.

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Acknowledgements

This work was supported by P01CA104106 from NIH to AD and BMP and DOD PC094499 from the US Army DOD to DS. We thank members of the Prostate Cancer Research Working group at UVA for helpful discussions.

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  1. Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA, USA

    D Sun, R Layer, A C Mueller, M A Cichewicz, M Negishi, B M Paschal & A Dutta

  2. Department of Computer Science, University of Virginia, Charlottesville, VA, USA

    R Layer

  3. Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA

    B M Paschal

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  1. D Sun
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Sun, D., Layer, R., Mueller, A. et al. Regulation of several androgen-induced genes through the repression of the miR-99a/let-7c/miR-125b-2 miRNA cluster in prostate cancer cells. Oncogene 33, 1448–1457 (2014). https://doi.org/10.1038/onc.2013.77

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