Abstract 1478: Gene-selective recruitment of NuRD drives chromatin reprogramming in cancer cells
Authors: Adone Mohd-Sarip, Diana Zatreanu, Jeroen A. Demmers, C Peter Verrijzer
Journal: Cancer Research (2018)

Abstract ATP-dependent chromatin remodelers are frequently mutated in cancers. However, the molecular basis of the association between mutations in specific remodeler subunits and particular types of cancer is poorly understood. To understand how remodelers are targeted in a cell-type specific manner, we aim to explore the mechanisms of the Nucleosome Remodeling and Deacetylase (NURD) complex during cancer progression. We recently showed that DOC1-dependent recruitment of NuRD reveals antagonism with SWI/SNF during epithelial-mesenchymal transition in oral cancer cells (Mohd-Sarip et al., 2017). It is instructive to compare the function of DOC1 in oral squamous cell carcinomas (OSCCs) with that of the SWI/SNF subunit SMARCB1/hSNF5 in malignant rhabdoid tumors (MRTs). MRTs are an extremely aggressive pediatric cancer caused by the loss of SMARCB1 (Kia et al., 2008). Although the loss of DOC1 in OSCCs or that of SMARCB1 in MRTs generates opposite epigenetic states of their target genes, in both cases, this is caused by failed remodeler recruitment. The loss of a single subunit, such as DOC1 or SMARCB1, does not abrogate all other remodeler functions. We suggest that subunit-dependent gene selection is a major cause of the association between the loss of specific remodeler subunits and particular types of cancer. Our results emphasize that gene control involves a dynamic equilibrium between opposing chromatin modulating enzymes rather than a static chromatin state. Disturbances in this balance can initiate a cascade of chromatin reprogramming events that drives oncogenesis. Such an intertwined system of epigenetic regulation suggests therapeutic strategies aimed at restoring the balance between antagonistic activities. Prompted by these findings, we will present an inclusive view of the protein regulatory network in order to gain a wholesome understanding of the molecular transactions and dynamic composition of NuRD complexes in specific cancer types. These were identified by immunopurifications using in-house antibodies followed by mass spectrometry. Our proteomic studies of the NuRD complex in flies (Reddy et al., 2010) and HeLa nuclear extracts suggest that mammalian NuRD share the same subunits with flies. Upon closer inspection, we found unanticipated novel interacting partners of NuRD and that they are altered in specific cancers namely prostate, pancreatic and ovarian. This will be followed by confirmation of the interactomes using cell-based and biochemistry assays in combination with genome-wide approaches, as well as potentially leading to the characterization of novel targets of NuRD. These findings will represent the types of multiprotein NuRD-like complexes that can form during cancer progression and how they are targeted to chromatin. Citation Format: Adone Mohd-Sarip, Diana Zatreanu, Jeroen A. Demmers, C Peter Verrijzer. Gene-selective recruitment of NuRD drives chromatin reprogramming in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1478.