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JAK signaling globally counteracts heterochromatic gene silencing

Nature Genetics volume 38, pages 1071–1076 (2006)Cite this article

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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Figure 1: Genetic mutations influence hopTum-l hematopoietic tumorigenicity.
Figure 2: Su(var)205, Su(var)3-9 and Rpd3 mutations enhance hopTum-l tumorigenicity without affecting JAK/STAT signaling.
Figure 3: JAK gain of function suppresses and loss of function enhances heterochromatic gene silencing.
Figure 4: JAK gain of function decreases, and loss of function increases, HP1 and H3mK9 localization on heterochromatin.
Figure 5: HP1 counteracts tumorigenesis induced by JAK/STAT 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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Authors and Affiliations

  1. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, 14642, New York, USA

    Song Shi, Healani C Calhoun, Fan Xia, Jinghong Li, Long Le & Willis X Li

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  1. Song Shi
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  2. Healani C Calhoun
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Contributions

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.

Note: Supplementary information is available on the Nature Genetics website.

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Correspondence to Willis X Li.

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The authors declare no competing financial interests.

Supplementary information

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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