DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition in Oral Cancer Cells

Adone Mohd-Sarip*, Miriam Teeuwssen, Alice G. Bot, Maria J. De Herdt, Stefan M. Willems, Robert J. Baatenburg de Jong, Leendert H.J. Looijenga, Diana Zatreanu, Karel Bezstarosti, Job van Riet, Edwin Oole, Wilfred F.J. van Ijcken, Harmen J.G. van de Werken, Jeroen A. Demmers, Riccardo Fodde, C. Peter Verrijzer

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

The Nucleosome Remodeling and Deacetylase (NURD) complex is a key regulator of cell differentiation that has also been implicated in tumorigenesis. Loss of the NURD subunit Deleted in Oral Cancer 1 (DOC1) is associated with human oral squamous cell carcinomas (OSCCs). Here, we show that restoration of DOC1 expression in OSCC cells leads to a reversal of epithelial-mesenchymal transition (EMT). This is caused by the DOC1-dependent targeting of NURD to repress key transcriptional regulators of EMT. NURD recruitment drives extensive epigenetic reprogramming, including eviction of the SWI/SNF remodeler, formation of inaccessible chromatin, H3K27 deacetylation, and binding of PRC2 and KDM1A, followed by H3K27 methylation and H3K4 demethylation. Strikingly, depletion of SWI/SNF mimics the effects of DOC1 re-expression. Our results suggest that SWI/SNF and NURD function antagonistically to control chromatin state and transcription. We propose that disturbance of this dynamic equilibrium may lead to defects in gene expression that promote oncogenesis.

Original languageEnglish
Pages (from-to)61-75
JournalCell Reports
Volume20
Issue number1
DOIs
Publication statusPublished - 05 Jul 2017

Keywords

  • CHD4
  • chromatin
  • DOC1/CDK2AP1
  • epigenetics
  • epithelial-mesenchymal transition
  • NURD
  • oral cancer
  • Polycomb
  • SWI/SNF

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Mohd-Sarip, A., Teeuwssen, M., Bot, A. G., De Herdt, M. J., Willems, S. M., Baatenburg de Jong, R. J., Looijenga, L. H. J., Zatreanu, D., Bezstarosti, K., van Riet, J., Oole, E., van Ijcken, W. F. J., van de Werken, H. J. G., Demmers, J. A., Fodde, R., & Verrijzer, C. P. (2017). DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition in Oral Cancer Cells. Cell Reports, 20(1), 61-75. https://doi.org/10.1016/j.celrep.2017.06.020