The transcriptional response to tumorigenic polarity loss in Drosophila

• Published in: eLife 2015-02, Vol.4
• Main Authors: Bunker, Brandon D, Nellimoottil, Tittu T, Boileau, Ryan M, Classen, Anne K, Bilder, David
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Cancer; Cell Polarity - genetics; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Developmental Biology and Stem Cells; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; epithelial cell; Fos protein; Gene expression; Gene Expression Profiling; Insects; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Kinases; Microscopy, Fluorescence; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oxidative stress; Polarity; Polycomb group proteins; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; Protein Kinase C - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA Interference; Signal Transduction; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription; Transcription, Genetic; transcriptome; tumor; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.03189

Loss of polarity correlates with progression of epithelial cancers, but how plasma membrane misorganization drives oncogenic transcriptional events remains unclear. The polarity regulators of the Drosophila Scribble (Scrib) module are potent tumor suppressors and provide a model for mechanistic investigation. RNA profiling of Scrib mutant tumors reveals multiple signatures of neoplasia, including altered metabolism and dedifferentiation. Prominent among these is upregulation of cytokine-like Unpaired (Upd) ligands, which drive tumor overgrowth. We identified a polarity-responsive enhancer in upd3, which is activated in a coincident manner by both JNK-dependent Fos and aPKC-mediated Yki transcription. This enhancer, and Scrib mutant overgrowth in general, are also sensitive to activity of the Polycomb Group (PcG), suggesting that PcG attenuation upon polarity loss potentiates select targets for activation by JNK and Yki. Our results link epithelial organization to signaling and epigenetic regulators that control tissue repair programs, and provide insight into why epithelial polarity is tumor-suppressive.