Sin3a acts through a multi-gene module to regulate invasion in Drosophila and human tumors.
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.
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, USA.
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Das
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Sangodkar
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Negre
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Narla
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Cagan
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018813:Multiple Endocrine Neoplasia Type 2a / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D015533:Transcriptional Activation; D051155:Wnt1 Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D051155:Wnt1 Protein; D051176:beta Catenin; C074622:wg protein, Drosophila; D051096:Proto-Oncogene Proteins c-ret; C416649:Ret protein, Drosophila; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D020742:rhoA GTP-Binding Protein