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A dosage-dependent pleiotropic role of Dicer in prostate cancer growth and metastasis

Oncogene volume 33, pages 3099–3108 (2014)Cite this article

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Abstract

Dicer is an RNase III enzyme essential for the maturation of the majority of microRNAs. Recent studies have revealed downregulation or hemizygous loss of Dicer in many tumor models and demonstrated that suppressing Dicer activity enhances tumorigenic activities of lung and breast cancer cells, which support Dicer as a haploinsufficient tumor suppressor in these cancer models. Surprisingly, we found that knocking down Dicer expression suppresses the growth and tumorigenic capacity of human prostate cancer cell lines, but enhances migratory capacities of some prostate cancer cell lines. Dicer is upregulated in human prostate cancer specimens, but lower Dicer expression portends a shorter time to recurrence. Complete ablation of Dicer activity in a Pten null mouse model for prostate cancer significantly halts tumor growth and progression, demonstrating that microRNAs have a critical role in maintaining cancer cell fitness. In comparison, hemizygous loss of Dicer in the same model also reduces primary tumor burden, but induces a more locally invasive phenotype and causes seminal vesicle obstruction at high penetrance. Disrupting Dicer activity leads to an increase in apoptosis and senescence in these models, presumably through upregulation of P16/INK4a and P27/Kip1. Collectively, these results highlight a pleotropic role of Dicer in tumorigenesis that is not only dosage-dependent but also tissue context-dependent.

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Acknowledgements

We thank Drs Lawrence Donehower and Jeffrey Rosen for critical comments, Dr Xiongbin Lu for sharing reagents. This work is supported by NIH R00 CA125937 (LX), Cancer Prevention Research Institute of Texas RP110005 (LX), NIH U01 CA141497 (MMI), and NIH P30 CA125123 (PI: Kent Osborne). This study was supported by National Cancer Institute, Cancer Prevention and Research Institute of Texas.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, TX, Houston, USA

    B Zhang, H Chen, L Zhang, M T Lewis & L Xin

  2. Department of Pathology and Immunology, Baylor College of Medicine, TX, Houston, USA

    O Dakhova, M M Ittmann & L Xin

  3. Dan L. Duncan Cancer Center, TX, Houston, USA

    Y Zhang, M T Lewis, C J Creighton, M M Ittmann & L Xin

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Zhang, B., Chen, H., Zhang, L. et al. A dosage-dependent pleiotropic role of Dicer in prostate cancer growth and metastasis. Oncogene 33, 3099–3108 (2014). https://doi.org/10.1038/onc.2013.281

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