Genetic dissection of signalling pathways that mediate iron-related tumor growth in a Drosophila model.

Iron dyshomeostasis is associated with various cancers. Here we explore the underlying mechanisms through which iron promotes tumor growth and metastasis using a Drosophila cancer model. In this model, cells iin the eye-antennal imaginal disc co-express oncogenic Raf gain-of-function and Scribbled loss-of-function mutants, leading to tumor formation. First, we show that dietary iron overload enhances tumor growth, invasiveness and mobility of cancer cells, whereas iron chelation suppresses these phenotypes. Consistently, RNA interference (RNAi)-mediated knockdown of dZIP13, a zinc transporter that transports iron into the secretory pathway, results in cytosolic iron accumulation and exacerbates the cancer-like phenotypes. Second, we show that the activity of a ten-eleven translocation DNA dioxygenase (TET), which enables DNA demethylation, correlates with cellular iron bioavailability, consistent with the known requirement of iron in the catalytic site of this enzyme. Third, we show that the TET enzyme transcriptionally regulates a histone methylase responsible for the H3K27me3 epigenetic mark. Fourth, we demonstrate that the iron-dependent DNA demethylation and subsequent histone trimethylation events activate the JAK/STAT signalling pathway, which promotes tumorigenesis, including the recruitment and proliferation of hemocytes to the malignant tissue. These findings reveal a novel tumor-suppressor function for dZIP13, while providing molecular mechanisms for iron-mediated tumor progression.