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MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial–mesenchymal transition

Oncogene volume 33, pages 1680–1689 (2014)Cite this article

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Abstract

The epithelial–mesenchymal transition (EMT) is activated in cancer cells by ZEB1, a member of the zinc finger/homeodomain family of transcriptional repressors. The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in human carcinoma cells. The present studies in breast cancer cells demonstrate that the oncogenic MUC1-C subunit induces expression of ZEB1 by a NF-κB (nuclear factor kappa B) p65-dependent mechanism. MUC1-C occupies the ZEB1 promoter with NF-κB p65 and thereby promotes ZEB1 transcription. In turn, ZEB1 associates with MUC1-C and the ZEB1/MUC1-C complex contributes to the transcriptional suppression of miR-200c, an inducer of epithelial differentiation. The co-ordinate upregulation of ZEB1 and suppression of miR-200c has been linked to the induction of EMT. In concert with the effects of MUC1-C on ZEB1 and miR-200c, we show that MUC1-C induces EMT and cellular invasion by a ZEB1-mediated mechanism. These findings indicate that (i) MUC1-C activates ZEB1 and suppresses miR-200c with the induction of EMT and (ii) targeting MUC1-C could be an effective approach for the treatment of breast and possibly other types of cancers that develop EMT properties.

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Acknowledgements

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA97098 and CA166480.

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Author notes

  1. R Ahmad

    Present address: 3Current address: College of Medicine, King Saud University, Riyadh, Saudi Arabia.,

  2. H Rajabi, M Alam and H Takahashi: These authors contributed equallly to this work.

Authors and Affiliations

  1. Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    H Rajabi, M Alam, H Takahashi, A Kharbanda, M Guha, R Ahmad & D Kufe

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  1. H Rajabi
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  2. M Alam
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Correspondence to D Kufe.

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Competing interests

Dr D Kufe is a founder of Genus Oncology and holds equity in the company. The remaining authors disclosed no potential conflicts of interest.

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Rajabi, H., Alam, M., Takahashi, H. et al. MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial–mesenchymal transition. Oncogene 33, 1680–1689 (2014). https://doi.org/10.1038/onc.2013.114

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