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Cell Rep. 2017 Jul 5;20(1):61-75. doi: 10.1016/j.celrep.2017.06.020.

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

Author information

1
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; Department of Biochemistry, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands. Electronic address: a.mohdsarip@qub.ac.uk.
2
Department of Pathology, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands.
3
Department of Biochemistry, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands.
4
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.
5
Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands.
6
Proteomics Centre, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands.
7
Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands; Department of Urology, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands.
8
Center for Biomics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands.
9
Department of Biochemistry, Erasmus University Medical Center, P.O. Box 1738, 3000 DR, Rotterdam, the Netherlands. Electronic address: c.verrijzer@erasmusmc.nl.

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.

KEYWORDS:

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

PMID:
28683324
DOI:
10.1016/j.celrep.2017.06.020
[Indexed for MEDLINE]
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