Abstract
The JAK/STAT pathway has pleiotropic roles in animal development, and its aberrant activation is implicated in multiple human cancers1,2,3. JAK/STAT signaling effects have been attributed largely to direct transcriptional regulation by STAT of specific target genes that promote tumor cell proliferation or survival. We show here in a Drosophila melanogaster hematopoietic tumor model, however, that JAK overactivation globally disrupts heterochromatic gene silencing, an epigenetic tumor suppressive mechanism4. This disruption allows derepression of genes that are not direct targets of STAT, as evidenced by suppression of heterochromatin-mediated position effect variegation. Moreover, mutations in the genes encoding heterochromatin components heterochromatin protein 1 (HP1) and Su(var)3-9 enhance tumorigenesis induced by an oncogenic JAK kinase without affecting JAK/STAT signaling. Consistently, JAK loss of function enhances heterochromatic gene silencing, whereas overexpressing HP1 suppresses oncogenic JAK-induced tumors. These results demonstrate that the JAK/STAT pathway regulates cellular epigenetic status and that globally disrupting heterochromatin-mediated tumor suppression is essential for tumorigenesis induced by JAK overactivation.
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Acknowledgements
We thank K. Larson and D. Guo for technical assistance; J. Birchler, S. Elgin, L. Wallrath, N. Reich, N. Perrimon, E. Bach and the Bloomington Drosophila Stock Center for various Drosophila strains and L. Silver-Morse for helpful comments on the manuscript. J.L. was a recipient of the Wilmot Cancer Research Fellowship. H.C.C. was a trainee of the Post-Baccalaureate Research Education Program (PREP) of the US National Institutes of Health. This study was supported by grants from the US National Institutes of Health (R01GM65774 and R01GM077046) and an American Cancer Society Research Scholar Grant (RSG-06-196-01-TBE) to W.X.L.
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The initial Df screen was performed by H.C.C., J.L. and L.L.; identification of modifier genes and phenotype assessment were performed by S.S.; F.X. contributed to the protein blot analysis. W.X.L. designed the study and wrote the paper.
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Supplementary Table 1
Modifiers of hopTum-1 tumorigenicity. (PDF 87 kb)
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Shi, S., Calhoun, H., Xia, F. et al. JAK signaling globally counteracts heterochromatic gene silencing. Nat Genet 38, 1071–1076 (2006). https://doi.org/10.1038/ng1860
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DOI: https://doi.org/10.1038/ng1860
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