Mrace Grant 2017

Dr. Jekyll and Mr. Hide: phenotypic plasticity and epigenetic control of EMT in oral cancer metastasis

Summary

One of the major surprises that came out of the cancer genome sequencing studies was the preponderance of mutations in chromatin remodelers in association with a very broad spectrum of carcinoma types. Although the underlying molecular mechanisms remain elusive, these findings support the crucial role for epigenetic regulation in human cancer, in particular in the context of EMT (epithelial to mesenchymal transition), its reverse process MET, cancer stemness, and resistance to chemotherapy. These represent the quintessential features of the metastasizing or migratory cancer stem cell (mCSC) as they confer it the Dr. Jekyll and Mr. Hide capacity to continuously adapt its identity as a function of its ever changing microenvironment in the long journey from primary lesion to metastatic site.

Loss of the DOC1 (deleted in oral cancer 1) subunit of the NuRD remodeling and deacetylase complex is associated with human oral squamous cell carcinoma (OSCC). In a collaborative network involving the departments of Otorhinolaryngology and Head and Neck Surgery, Pathology, and Biochemistry, we found that tumor suppression by DOC1 regulates EMT/MET in the squamous oral epithelium through NURD-dependent repression of the Twist gene, i.e. one of the master regulators of EMT1. DOC1 mediates the recruitment of NURD to the Twist genes, thus triggering comprehensive epigenetic reprogramming, including eviction of the SWI/SNF remodeler and formation of closed chromatin. Our results have highlighted the relevance of epigenetic regulation in the establishment and maintenance of a dynamic equilibrium between opposing chromatin modulating enzymes. Such an intertwined system of epigenetic control opens novel opportunities for the development of therapeutic strategies aimed at restoring the balance between antagonistic activities.

The main goal of this proposal is to elucidate the cooperative and antagonistic interplay between the NURD, Polycomb and SWI/SNF chromatin remodelers during the malignant progression of oral squamous cell cancer. To this aim we will take advantage of an interdisciplinary approach including tumor immunohistochemistry, whole genome epigenetic (ChIPseq), gene expression (RNAseq) analysis, mouse models, 3D organoid cultures, and CRISPR/CAS9 genome editing technologies. We anticipate that our results will not only elucidate the role of chromatin remodelers in EMT, malignant progression and metastasis in oral cancer, but also provide general insights in the roll of epigenetic balance in (cancer) stem cell differentiation.

Erasmus MC

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