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

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

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

Authors

Adone Mohd-Sarip¹, Miriam Teeuwssen², Alice G Bot³, Maria J De Herdt⁴, Stefan M Willems⁵, Robert J Baatenburg de Jong⁴, Leendert H J Looijenga², Diana Zatreanu³, Karel Bezstarosti⁶, Job van Riet⁷, Edwin Oole⁸, Wilfred F J van Ijcken⁸, Harmen J G van de Werken⁷, Jeroen A Demmers⁶, Riccardo Fodde², C Peter Verrijzer⁹

Affiliations

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: [email protected].
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: [email protected].

PMID: 28683324
DOI: 10.1016/j.celrep.2017.06.020

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Cell Line, Tumor
Cells, Cultured
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone / metabolism*
Epigenesis, Genetic
Epithelial-Mesenchymal Transition*
Gene Expression Regulation, Neoplastic
Histones / metabolism
Humans
Intracellular Signaling Peptides and Proteins / metabolism*
Methylation
Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism*
Mouth Neoplasms / genetics
Mouth Neoplasms / metabolism*
Protein Processing, Post-Translational
Transcription Factors / metabolism*

Substances

Chromosomal Proteins, Non-Histone
FILIP1L protein, human
Histones
Intracellular Signaling Peptides and Proteins
SWI-SNF-B chromatin-remodeling complex
Transcription Factors
Mi-2 Nucleosome Remodeling and Deacetylase Complex