NuRD Chromatin Remodeling Complex Coordinates the Epithelial-Mesenchymal Transition via Transcriptional Regulation of Major EMT Regulators

Abstract

Cancer is a major global health concern due to its increasing prevalence and the critical role of metastasis in tumor recurrence and cancer-related deaths. Metastasis, driven by epithelial-mesenchymal transition (EMT), enables cancer cells to acquire invasive and stem cell-like properties. Cancer stem cells (CSCs) within tumors play a crucial role in tumor initiation, progression, drug resistance, and metastasis. CSCs can emerge from cancer cells undergoing EMT, enhancing their invasiveness. Understanding the interplay between metastasis, EMT, and CSCs is vital for developing effective cancer therapies. This study proposes a strategy to eliminate mesenchymal CSCs by converting them into non-tumorigenic counterparts. Knockdown of MBD2 or p66α, components of the MBD2-NuRD complex, activates FOXA1, FBXO31, and LARP7, leading to mesenchymal-to-epithelial transition (MET) in human triple-negative breast cancer cells (MDA-MB-231 LM1) and CD44+ colon cancer cells (HCT116). Downregulating MBD2 and p66α results in the derepression of epithelial regulators through complex disentanglement or epigenetic reprogramming of the repressive MBD2-NuRD complex into the active MBD2-free NuRD complex. This promotes epithelial differentiation and loss of tumorigenic potential. This thesis provides evidence for inducing MET as a differentiation therapy for CSCs and highlights the role of the NuRD complex in enforcing and maintaining the epithelial state.