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Oncogene
Article
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Oncogene
Article . 2012 . Peer-reviewed
License: Springer TDM
Data sources: Crossref
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Sin3a acts through a multi-gene module to regulate invasion in Drosophila and human tumors

Authors: T K, Das; J, Sangodkar; N, Negre; G, Narla; R L, Cagan;

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

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.

Keywords

Transcriptional Activation, Lung Neoplasms, Proto-Oncogene Proteins c-ret, JNK Mitogen-Activated Protein Kinases, Multiple Endocrine Neoplasia Type 2a, Wnt1 Protein, Inhibitor of Apoptosis Proteins, Gene Expression Regulation, Neoplastic, Repressor Proteins, Sin3 Histone Deacetylase and Corepressor Complex, Cell Transformation, Neoplastic, Cell Movement, Cell Line, Tumor, Animals, Drosophila Proteins, Humans, Drosophila, Neoplasm Invasiveness, beta Catenin, Signal Transduction

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
58
Top 10%
Top 10%
Top 10%
bronze