The Jumonji-C Histone Lysine Demethylase KDM3B Senses Cellular Iron to Regulate Anabolism Through mTORC1

Iron is an essential nutrient for anabolic and catabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolism are unclear. Here, we report that the iron-binding histone-demethylase KDM3B is an iron sensor for mTORC1. Iron starvation results in genome-wide H3K9me2 hyper-methylation, suppression of leucine-signaling and RAPTOR expression, and mTORC1 inactivity despite sufficient levels of other nutrients. This process occurs in vivo, and is conserved throughout the eukaryotic kingdoms. Elevated expression of KDM3B targets are associated with reduced survival in a subset of cancers, and iron chelation represses mTORC1 in patient-derived tumor cells and sensitizes cancer cells to chemotherapy. Together, these data demonstrate a novel mechanism of iron sensing by KDM3B and repression of mTORC1 activity through disrupted leucine-signaling and RAPTOR downregulation. Due to ancestral eukaryotes sharing homologues of KDMs and mTORC1 core components, this pathway likely predated the emergence of the other nutrient sensors for mTORC1.