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Sin3a acts through a multi-gene module to regulate invasion in Drosophila and human tumors

Oncogene volume 32, pages 3184–3197 (2013)Cite this article

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Abstract

Chromatin remodeling proteins regulate multiple aspects of cell homeostasis, making them ideal candidates for misregulation in transformed cells. Here, we explore Sin3A, a member of the Sin3 family of proteins linked to tumorigenesis that are thought to regulate gene expression through their role as histone deacetylases (HDACs). We identified Drosophila Sin3a as an important mediator of oncogenic Ret receptor in a fly model of Multiple Endocrine Neoplasia Type 2. Reducing Drosophila Sin3a activity led to metastasis-like behavior and, in the presence of Diap1, secondary tumors distant from the site of origin. Genetic and Chip-Seq analyses identified previously undescribed Sin3a targets including genes involved in cell motility and actin dynamics, as well as signaling pathways including Src, Jnk and Rho. A key Sin3a oncogenic target, PP1B, regulates stability of β-Catenin/Armadillo: the outcome is to oppose T-cell factor (TCF) function and Wg/Wnt pathway signaling in both fly and mammalian cancer cells. Reducing Sin3A strongly increased the invasive behavior of A549 human lung adenocarcinoma cells. We show that Sin3A is downregulated in a variety of human tumors and that Src, JNK, RhoA and PP1B/β-Catenin are regulated in a manner analogous to our Drosophila models. Our data suggest that Sin3A influences a specific step of tumorigenesis by regulating a module of genes involved in cell invasion. Tumor progression may commonly rely on such ‘modules of invasion’ under the control of broad transcriptional regulators.

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Acknowledgements

We thank members of the Cagan Lab for sharing reagents, information, and helpful advice and Justin Graves for providing help mapping UAS-dRetMEN2 transgenic flies. This work was supported by NIH/NCI grants R01-CA084309 and R01-CA109730 to RC and American Cancer Society Fellowship grant 120886-PFM-11-137-01-DDC to TD.

Author contributions: T.D. and R.C. designed the project. T.D. performed the in vivo Drosophila work, the transient siRNA transfection and western analysis on cell lines, and analyzed the ONCOMINE data. T.D. and J.S. performed wound healing assay. J.S. performed MTT assay. G.N. and J.S. generated and analyzed patient tumor expression data. N.N. generated the ChIP-seq data. T.D. and R.C. analyzed the data and wrote the manuscript.

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Authors and Affiliations

  1. Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, USA

    T K Das & R L Cagan

  2. Department of Genetics, Mount Sinai School of Medicine, New York, NY, USA

    J Sangodkar & G Narla

  3. Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA

    N Negre

  4. Department of Medicine, Division of Hematology-Oncology, Mount Sinai School of Medicine, New York, NY, USA

    G Narla

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Correspondence to R L Cagan.

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Das, T., Sangodkar, J., Negre, N. et al. Sin3a acts through a multi-gene module to regulate invasion in Drosophila and human tumors. Oncogene 32, 3184–3197 (2013). https://doi.org/10.1038/onc.2012.326

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