Targeting <scp>EZH2</scp> reverses thyroid cell dedifferentiation and enhances iodide uptake in anaplastic thyroid cancer

Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy characterized by dedifferentiation and radioiodine refractoriness. We investigated whether EZH2-mediated H3K27me3 deposition represses thyroid differentiation genes (TDGs) in ATC cells. Online ChIP-seq analyses and CUT&RUN confirmed EZH2/H3K27me3 enrichment at key TDGs (SLC5A5, NKX2-1, TSHR, FOXE1, TPO). Pharmacological inhibition of EZH2 with EPZ6438 reactivated TDG expression in RAS and BRAF-mutated ATC cell lines and partially restored iodide uptake. Co-treatment with the MEK1/2 inhibitor U0126 further enhanced TDG expression, consistent with MAPK-dependent regulation of EZH2. These findings reveal EZH2 as a mediator of ATC dedifferentiation and highlight its inhibition as a potential strategy to restore thyroid function and sensitize tumors to radioiodine. Impact statement This study reveals how EZH2-driven epigenetic remodeling controls thyroid cell dedifferentiation and loss of iodide uptake in anaplastic thyroid cancer. Our findings provide new mechanistic insights and highlight an FDA-approved drug with repurposing potential, advancing both anaplastic thyroid cancer biology research and therapeutic perspectives.