title: The transcriptional response to tumorigenic polarity loss in Drosophila.
abstract: 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.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Brandon D
authors.initials: BD
authors.lastname: Bunker
authors.affiliation: University of Southern California, Department of Biological Sciences, Los Angeles, United States.
authors.forename: Tittu T
authors.initials: TT
authors.lastname: Nellimoottil
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Boileau
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Classen
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: David
authors.initials: D
authors.lastname: Bilder
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D016764:Cell Polarity / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; C404683:Scrib protein, Drosophila; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C558732:Upd3 protein, Drosophila; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C115015:PKC-3 protein; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases
keywords: D. melanogaster; cancer; developmental biology; epithelial cells; polarity; stem cells; transcriptome; tumor