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A tumor suppressor activity of Drosophila Polycomb genes mediated by JAK-STAT signaling

Abstract

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 cancer1,2. 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.

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Figure 1: PRC1 components are fly tumor suppressors.
Figure 2: JAK-STAT signaling is ectopically activated in PRC1 mutant tissue.
Figure 3: Unpaired is a direct target of PcG-mediated silencing in imaginal discs.
Figure 4: JAK-STAT signaling drives PRC1 mutant overgrowth.

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Acknowledgements

We thank P. Lueras for assistance with genetic screening, C. Marconett for help with genetic mapping, members of the Vance and Barton laboratories for assistance with quantitative PCR, and G. Cavalli and A.-M. Martinez for communication before publication. We further thank the Bloomington Stock Center and the Developmental Studies Hybridoma Bank, as well as J. Treisman, R. Emmons, I. Hariharan, J. Simon, J. Mueller, E. Bach, J. Parrish, R. Mann, G. Halder, N. Perrimon, D. Harrison and B. Mathey-Prevot, for kindly providing flies and reagents. The authors are grateful to members of the Bilder, Hariharan, Karpen, Speed and Biggin labs for their invaluable input and help. This work was supported by grants from the US National Institutes of Health (R01 GM068675) and The Burroughs Welcome Trust to D.B. A.K.C was supported by a fellowship from Jane Coffin Childs Memorial Foundation. K.F.H. holds Career Development Awards from the International Human Frontier Science Program Organization and the National Health and Medical Research Council of Australia. T.V. was supported by a fellowship from the American Heart Association.

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A.K.C. and D.B. conceived the study and wrote the paper. A.K.C. carried out the experiments and analyzed the data. B.D.B. carried out the molecular and T.V. the genetic mapping of the P3C allele, which was isolated and initially characterized by K.F.H.

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Correspondence to David Bilder.

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Classen, AK., Bunker, B., Harvey, K. et al. A tumor suppressor activity of Drosophila Polycomb genes mediated by JAK-STAT signaling. Nat Genet 41, 1150–1155 (2009). https://doi.org/10.1038/ng.445

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