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.
Keywords:
D. melanogaster; cancer; developmental biology; epithelial cells; polarity; stem cells; transcriptome; tumor.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Cell Polarity / genetics*
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Cell Proliferation / genetics
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Drosophila Proteins / genetics*
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Drosophila Proteins / metabolism
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Drosophila melanogaster / genetics*
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Drosophila melanogaster / metabolism
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Gene Expression Profiling
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JNK Mitogen-Activated Protein Kinases / metabolism
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Membrane Proteins
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Microscopy, Fluorescence
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Mutation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Polycomb-Group Proteins / genetics
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Polycomb-Group Proteins / metabolism
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Protein Kinase C / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription, Genetic*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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YAP-Signaling Proteins
Substances
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Drosophila Proteins
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Membrane Proteins
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Nuclear Proteins
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Polycomb-Group Proteins
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Scrib protein, Drosophila
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Trans-Activators
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Tumor Suppressor Proteins
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Upd3 protein, Drosophila
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YAP-Signaling Proteins
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Yki protein, Drosophila
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PKC-3 protein
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Protein Kinase C
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JNK Mitogen-Activated Protein Kinases