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Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein

Oncogene volume 29, pages 4980–4988 (2010)Cite this article

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Abstract

Oncogenic c-Myc has been described to modulate the expression of a subset of microRNAs (miRNAs), which include miR-22; however, the mechanism through which a miRNA controls c-Myc activity remains unclear. Here we report a novel anti-c-Myc function mediated by miR-22. Ectopically expressed miR-22 inhibited cell proliferation and anchorage-independent growth of human cancer cell lines. Microarray screening and western analyses revealed that miR-22 repressed the c-Myc-binding protein MYCBP, a positive regulator of c-Myc. Consistent with this, reporter assays showed that miR-22-mediated MYCBP gene suppression largely depends on the conserved miR-22 target site within the MYCBP 3′-untranslational region (3′UTR), implying that MYCBP mRNA is a direct miR-22 target. Depletion of MYCBP using small interfering RNA (siRNA) recapitulated the miR-22-induced anti-growth effect on tumor cells, whereas ectopically expressed MYCBP rescued cells from the growth suppression mediated by miR-22. Moreover, repression of MYCBP by miR-22 downregulated a panel of E-box-containing c-Myc target genes. Our results suggest that miR-22 acts as a tumor suppressor through direct repression of MYCBP expression and subsequent reduction of oncogenic c-Myc activities. As c-Myc inhibits the expression of miR-22, we propose a novel positive feedback loop formed by oncogenic c-Myc to accelerate cell proliferation by suppressing miR-22, a potent inhibitor of MYCBP.

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Acknowledgements

We thank Tianjing Cai for excellent technical assistance, and Dr Iain C Bruce for critical reading of the paper. This work was supported by the National High-tech R&D Program of China (2007AA02Z165, 2008DFA30770), the National Basic Research Program of China (2007CB512100), the National Natural Science Foundation of China (30873187, 30771085 and 30871385) and by grants from the Department of Education of China (20070001011 and 200800010019).

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  1. Institute of Molecular Medicine, Peking University, Beijing, China

    J Xiong, Q Du & Z Liang

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  1. J Xiong
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  2. Q Du
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Correspondence to Z Liang.

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Xiong, J., Du, Q. & Liang, Z. Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein. Oncogene 29, 4980–4988 (2010). https://doi.org/10.1038/onc.2010.241

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