Endocrine Abstracts

Radioiodine therapy (RAI): which is the cornerstone of the treatment of distant metastasis from differentiated thyroid cancers (DTC), is based on the expression of the iodine transporter NIS. The majority of DTC are papillary with BRAF^V600E mutation in 45% to 60% of cases. This mutation is associated with RAI refractory DTC with a low NIS expression and a low differentiation score. The absence of RAI uptake is a major challenge for the treatment of patients. A promising approach for the treatment of RAI-refractory patients is to re-enhance RAI uptake by promoting tumor redifferentiation. We showed that BRAF^V600E controls NADPH oxidase NOX4 and that NOX4-derived ROS contribute to NIS repression. Deletion of NOX4 promotes reactivation of NIS. This reversibility suggests a contribution of an epigenetic mechanism. Our hypothesis is that NOX4 generates specific oxidative DNA damage, promoting longer retention of epigenetic modifiers, such as DNMTs, at sites of DNA damage via the interaction with DNA repair proteins, contributing to stably preventing the transcription of genes from interfering with the repair process Our objectives are 1- to determine the molecular and mechanistic events induced by NOX4-derived ROS that contribute to the reversible regulation of genes involved in differentiation/dedifferentiation process and 2- to evaluate the role of NOX4 in the resistance mechanism to BRAF/MEK inhibitors. Our data suggest a key role of NOX4 in oxidative DNA damage, which promotes the recruitment to chromatin of an epigenetic complex in which DNA methyl transferase 1 (DNMT1) and the DNA mismatch repair system (MMR) cooperate.