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miR-26a enhances miRNA biogenesis by targeting Lin28B and Zcchc11 to suppress tumor growth and metastasis

Oncogene volume 33, pages 4296–4306 (2014)Cite this article

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Abstract

Human cancers often exhibit attenuated microRNA (miRNA) biogenesis and global underexpression of miRNAs; thus, targeting the miRNA biogenesis pathway represents a novel strategy for cancer therapy. Here, we report that miR-26a enhances miRNA biogenesis, which acts as a common mechanism partially accounting for miR-26a function in diverse cancers including melanoma, prostate and liver cancer. miR-26a was broadly reduced in multiple cancers, and overexpression of miR-26a significantly suppressed tumor growth and metastasis both in vitro and in vivo, including melanoma, prostate and liver cancers. Notably, miR-26a overexpression was accompanied by global upregulation of miRNAs, especially let-7, and let-7 expression was concordant with miR-26a expression in cancer cell lines, xenograft tumors and normal human tissues, underscoring their biological relevance. We showed that miR-26a directly targeted Lin28B and Zcchc11—two critical repressors of let-7 maturation. Furthermore, we have demonstrated that Zcchc11 promoted tumor growth and metastasis, and it was prominently overexpressed in human cancers. Our findings thus provide a novel mechanism by which a miRNA acts as a modulator of miRNA biogenesis. These results also define a role of the miR-26a and Zcchc11 in tumorigenesis and metastasis and have implications to develop new strategies for cancer therapy.

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Acknowledgements

We thank Drs Arthur Riggs and Rama Natarajan for reviewing the manuscript, Dr Kyle Sousa and other members of the Huang laboratory for their helpful discussions and Dr Keely Walker for editing the manuscript. This work was supported by the National Cancer Institute (P30 CA033572) and the American Cancer Society (RSG-11-132-01-CCE).

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Authors and Affiliations

  1. Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA

    X Fu, Z Meng, X Wang, W Han, G Lou, X Wang, F Lou & W Huang

  2. Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA

    Z Meng, Y Yen, H Yu, R Jove & W Huang

  3. Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA

    W Liang, Y Tian & R Jove

  4. Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA

    Y Yen

  5. Department of Cancer Immunotherapy and Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA

    H Yu

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Correspondence to W Huang.

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Fu, X., Meng, Z., Liang, W. et al. miR-26a enhances miRNA biogenesis by targeting Lin28B and Zcchc11 to suppress tumor growth and metastasis. Oncogene 33, 4296–4306 (2014). https://doi.org/10.1038/onc.2013.385

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