A tumor suppressive activity of Drosophila Polycomb genes mediated by JAK/STAT signaling

A prevailing paradigm posits that Polycomb Group (PcG) proteins maintain stem cell identity by repressing differentiation genes, and abundant evidence points to an oncogenic role for PcG in human cancer 1,2. Here we demonstrate using Drosophila that a conventional PcG complex can also have a potent tumor suppressive activity. Mutations in all core PRC1 components cause dramatic hyperproliferation of eye imaginal tissue, accompanied by deregulation of epithelial architecture. The mitogenic JAK/STAT pathway is strongly and specifically activated in mutant tissue; activation is driven by transcriptional upregulation of Unpaired (Upd) family ligands. We show that upd genes are direct targets of PcG-mediated repression in imaginal discs. Ectopic JAK/STAT activity is sufficient to induce overproliferation, while reduction of JAK/STAT activity suppresses the PRC1 mutant tumor phenotype. These findings show that PcG proteins can restrict growth directly by silencing mitogenic signaling pathways, shedding light onto an epigenetic mechanism underlying tumor suppression.