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MUC1-C activates BMI1 in human cancer cells

Oncogene volume 36, pages 2791–2801 (2017)Cite this article

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Abstract

B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a component of the polycomb repressive complex 1 (PRC1) complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overexpressed in human carcinoma cells and has been linked to their self-renewal. There is no known relationship between MUC1-C and BMI1 in cancer. The present studies demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism in breast and other cancer cells. In addition, we show that MUC1-C blocks miR-200c-mediated downregulation of BMI1 expression. The functional significance of this MUC1-C→BMI1 pathway is supported by the demonstration that targeting MUC1-C suppresses BMI1-induced ubiquitylation of H2A and thereby derepresses homeobox HOXC5 and HOXC13 gene expression. Notably, our results further show that MUC1-C binds directly to BMI1 and promotes occupancy of BMI1 on the CDKN2A promoter. In concert with BMI1-induced repression of the p16INK4a tumor suppressor, we found that targeting MUC1-C is associated with induction of p16INK4a expression. In support of these results, analysis of three gene expresssion data sets demonstrated highly significant correlations between MUC1-C and BMI1 in breast cancers. These findings uncover a previously unrecognized role for MUC1-C in driving BMI1 expression and in directly interacting with this stem cell factor, linking MUC1-C with function of the PRC1 in epigenetic gene silencing.

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Accession codes

Accessions

Gene Expression Omnibus

Abbreviations

BMI1:

B-cell-specific Moloney murine leukemia virus integration site 1

PRC1:

polycomb repressive complex 1

CSCs:

cancer stem-like cells

EMT:

epithelial–mesenchymal transition

DSB:

double-stranded DNA break

MUC1:

mucin 1

MUC1-C:

MUC1-C-terminal subunit

DNMT:

DNA methyltransferase

DOX:

doxycycline.

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Acknowledgements

This work was supported by Grants from the National Cancer Institute of the National Institutes of Health under award numbers CA97098 and CA166480 and by the Lung Cancer Research Foundation. The authors thank Dr Goberdhan P Dimri, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC for kindly providing the pGL-BMI1PrWT and pGL-BMI1PrMut reporter vectors.

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Author notes

  1. Y Suzuki

    Present address: 2Current address: Department of Gastroenterological Surgery, Osaka Police Hospital, Kitayama-Cho 10-31 Tennoji, Osaka City, Osaka 543-0035, Japan.,

  2. R Ahmad

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

Authors and Affiliations

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

    M Hiraki, T Maeda, A Bouillez, M Alam, A Tagde, K Hinohara, Y Suzuki, T Markert, M Miyo, K Komura, R Ahmad, H Rajabi & D Kufe

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Correspondence to D Kufe.

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DK holds equity in Genus Oncology and is a consultant to the company. The remaining authors declare no conflict of interest.

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Hiraki, M., Maeda, T., Bouillez, A. et al. MUC1-C activates BMI1 in human cancer cells. Oncogene 36, 2791–2801 (2017). https://doi.org/10.1038/onc.2016.439

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