SETMAR Facilitates the Differentiation of Thyroid Cancer by Regulating SMARCA2‐Mediated Chromatin Remodeling

Abstract Thyroid cancer is the most common type of endocrine cancer, and most patients have a good prognosis. However, the thyroid cancer differentiation status strongly affects patient response to conventional treatment and prognosis. Therefore, exploring the molecular mechanisms that influence the differentiation of thyroid cancer is very important for understanding the progression of this disease and improving therapeutic options. In this study, SETMAR as a key gene that affects thyroid cancer differentiation is identified. SETMAR significantly regulates the proliferation, epithelial‐mesenchymal transformation (EMT), thyroid differentiation‐related gene expression, radioactive iodine uptake, and sensitivity to MAPK inhibitor‐based redifferentiation therapies of thyroid cancer cells. Mechanistically, SETMAR methylates dimethylated H3K36 in the SMARCA2 promoter region to promote SMARCA2 transcription. SMARCA2 can bind to enhancers of the thyroid differentiation transcription factors (TTFs) PAX8, and FOXE1 to promote their expression by enhancing chromatin accessibility. Moreover, METTL3‐mediated m6A methylation of SETAMR mRNA is observed and showed that this medication can affect SETMAR expression in an IGF2BP3‐dependent manner. Finally, the METTL3‐14‐WTAP activator effectively facilitates the redifferentiation of thyroid cancer cells via the SETMAR‐SMARCA2‐TTF axis utilized. The research provides novel insights into the molecular mechanisms underlying thyroid cancer dedifferentiation and provides a new approach for therapeutically promoting redifferentiation.