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.

CHD4, chromatin, DOC1/CDK2AP1, epigenetics, epithelial-mesenchymal transition, NURD, oral cancer, Polycomb, SWI/SNF,
Cell Reports
Erasmus MC: University Medical Center Rotterdam

Mohd-Sarip, A, Teeuwssen, M, Bot, A.G, de Herdt, M.J, Willems, S.M, Baatenburg de Jong, R.J, … 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. doi:10.1016/j.celrep.2017.06.020