A “ tug-of-war ” between the NuRD and SWI/SNF chromatin remodelers regulates the coordinated activation of Epithelial-Mesenchymal Transition and inflammation in oral cancer

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Abstract Phenotypic plasticity and inflammation, two well-established hallmarks of cancer, play key roles in local invasion and distant metastasis by enabling rapid adaptation of tumor cells to dynamic micro- environmental changes. Here, we show that in oral squamous carcinoma cell carcinoma (OSCC), the competition between the NuRD and SWI/SNF chromatin remodeling complexes plays a pivotal role in regulating both epithelial-mesenchymal plasticity (EMP) and inflammation. By perturbing these complexes, we demonstrate their opposing downstream effects on inflammatory pathways and EMP regulation. In particular, downregulation of the BRG1-specific SWI/SNF complex deregulates key inflammatory genes such as TNF-α and IL6 in opposite ways when compared with loss of CDK2AP1, a key member of the NuRD complex. We show that CDK2AP1 genetic ablation triggers a pro-inflammatory secretome encompassing several chemo- and cytokines thus promoting the recruitment of monocytes into the tumor microenvironment (TME). Furthermore, CDK2AP1 deletion stimulates their differentiation into M2-like macrophages, as also validated on tumor microarrays from OSCC patient- derived tumor samples. Further analysis of the inverse correlation between CDK2AP1 expression and TME immune infiltration revealed specific downstream effects on CD68 + macrophage abundance and localization. Our study sheds light on the role of chromatin remodeling complexes in OSCC locoregional invasion and points at the potential of CDK2AP1 and other members of the NuRD and SWI/SNF chromatin remodeling complexes as prognostic markers and therapeutic targets.

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