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
Affiliations
Adone Mohd-Sarip
Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7BL, UK, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Miriam Teeuwssen
Department of Pathology, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Alice G. Bot
Department of Biochemistry, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Maria J. De Herdt
Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC Cancer Institute, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Stefan M. Willems
Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands
Robert J. Baatenburg de Jong
Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC Cancer Institute, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Leendert H.J. Looijenga
Department of Pathology, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Diana Zatreanu
Department of Biochemistry, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Karel Bezstarosti
Proteomics Centre, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Job van Riet
Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Edwin Oole
Center for Biomics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Wilfred F.J. van Ijcken
Center for Biomics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Harmen J.G. van de Werken
Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Jeroen A. Demmers
Proteomics Centre, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
Riccardo Fodde
Department of Pathology, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
C. Peter Verrijzer
Department of Biochemistry, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands
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.
