A tumor suppressor 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 proteins in human cancer. Here we show using Drosophila melanogaster that a conventional PcG complex can also have a potent tumor suppressor activity. Mutations in any core PRC1 component cause pronounced 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, also known as Outstretched, Os) family ligands. We show here that upd genes are direct targets of PcG-mediated repression in imaginal discs. Ectopic JAK-STAT activity is sufficient to induce overproliferation, whereas 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 on an epigenetic mechanism underlying tumor suppression.
Classen
Anne-Kathrin
AK
Department of Molecular and Cellular Biology, University of California, Berkeley, California, USA.
Bunker
Brandon D
BD
Harvey
Kieran F
KF
Vaccari
Thomas
T
Bilder
David
D
D000818:Animals; D049109:Cell Proliferation; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D005123:Eye / Q000166:cytology / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction
D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D050791:STAT Transcription Factors; D053612:Janus Kinases