NOX4 prevents the recruitment of PAX8 and NKX2.1 to chromatin in BRAF-mutated thyroid cancer cells

Radioiodine (RAI) therapy, used for treating thyroid cancers, hinges on the expression of the Sodium Iodide Symporter (NIS). The majority of differentiated thyroid cancers (DTCs) are papillary, with a BRAF ^V600E mutation. This mutation correlates with an absence of RAI uptake, due to low NIS expression and a low differentiation score. NADPH oxidase 4 (NOX4)-derived ROS contribute to NIS repression in BRAF ^V600E -mutated thyroid cancer cells. Depleting NOX4 enhances the reactivation of NIS. This reversibility implies an epigenetic mechanism’s contribution. Our findings indicate that NOX4 generates oxidative DNA damage in BRAF ^V600E -mutated thyroid cancer cells. DNA repair proteins such as OGG1 and MSH2/MSH6 proteins, in cooperation with DNMT1, turn these damages into transcription-blocking damages. This prevents the binding of PAX8 and NKX2.1 – two key transcription factors involved in thyroid differentiation – to the chromatin. Co-inhibition of the MAPK pathway, which regulates MSH2/MSH6 and DNMT1 expressions, and the TGF-β1 pathway, which regulates NOX4 expression, fortifies the recruitment of the two transcription factors to the chromatin. Collectively, our findings present a molecular basis for NOX4’s role in thyroid dedifferentiation.